NM_001136193.2(FASTKD2):c.149A>G (p.Lys50Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: May 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000442317.41

Allele description

NM_001136193.2(FASTKD2):c.149A>G (p.Lys50Arg)

Gene:

FASTKD2:FAST kinase domains 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q33.3

Genomic location:

Preferred name:

NM_001136193.2(FASTKD2):c.149A>G (p.Lys50Arg)

HGVS:

NC_000002.12:g.206766842A>G
NG_008984.1:g.6455A>G
NM_001136193.2:c.149A>GMANE SELECT
NM_001136194.2:c.149A>G
NM_014929.4:c.149A>G
NP_001129665.1:p.Lys50Arg
NP_001129666.1:p.Lys50Arg
NP_055744.2:p.Lys50Arg
NP_055744.2:p.Lys50Arg
NC_000002.11:g.207631566A>G
NM_014929.3:c.149A>G

Protein change:

K50R

Links:

dbSNP: rs141447598

NCBI 1000 Genomes Browser:

rs141447598

Molecular consequence:

NM_001136193.2:c.149A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001136194.2:c.149A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014929.4:c.149A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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PREDICTED: Homo sapiens protein phosphatase methylesterase 1 (PPME1), transcript...
PREDICTED: Homo sapiens protein phosphatase methylesterase 1 (PPME1), transcript variant X2, mRNA
gi|2217283339|ref|XM_017017913.3|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000510732	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 25, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000609021	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (May 1, 2024)	germline	clinical testing	Citation Link,
SCV000728411	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Dec 10, 2019)	germline	clinical testing	Citation Link,
SCV000802777	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Uncertain significance (Feb 25, 2016)	unknown	clinical testing
SCV001040143	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001552474	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	11	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000510732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Converted during submission to Uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.003193	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000609021.28

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	not provided

Description

FASTKD2: BP4, BS2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		11	not provided	not provided	not provided

From GeneDx, SCV000728411.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is associated with the following publications: (PMID: 25842392, 25842391, 25497598)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV000802777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001040143.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552474.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The FASTKD2 p.Lys50Arg variant was identified in 1 of 70 proband chromosomes (frequency: 0.0143) from individuals with ataxia (Pyle_2014_PMID: 25497598). The variant was identified in dbSNP (ID: rs141447598) and ClinVar (classified as likely benign by GeneDx and Invitae, and as uncertain significance by Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, CeGaT Praxis fuer Humangenetik Tuebingen, and Mayo Clinic). The variant was identified in control databases in 761 of 279634 chromosomes (2 homozygous) at a frequency of 0.002721 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 114 of 25062 chromosomes (freq: 0.004549), European (non-Finnish) in 535 of 128174 chromosomes (freq: 0.004174), Other in 23 of 7130 chromosomes (freq: 0.003226), Latino in 53 of 34698 chromosomes (freq: 0.001527), African in 17 of 24846 chromosomes (freq: 0.000684), South Asian in 15 of 29724 chromosomes (freq: 0.000505), Ashkenazi Jewish in 2 of 10180 chromosomes (freq: 0.000197), and East Asian in 2 of 19820 chromosomes (freq: 0.000101). The p.Lys50 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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