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NM_005188.4(CBL):c.107ACC[8] (p.His42dup) AND not specified

Germline classification:
Benign/Likely benign (4 submissions)
Last evaluated:
Jan 4, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000038350.18

Allele description [Variation Report for NM_005188.4(CBL):c.107ACC[8] (p.His42dup)]

NM_005188.4(CBL):c.107ACC[8] (p.His42dup)

Genes:
LOC130006895:ATAC-STARR-seq lymphoblastoid silent region 3975 [Gene]
CBL:Cbl proto-oncogene [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
11q23.3
Genomic location:
Preferred name:
NM_005188.4(CBL):c.107ACC[8] (p.His42dup)
Other names:
p.His42_Leu43insHis
HGVS:
  • NC_000011.10:g.119206524ACC[8]
  • NG_016808.1:g.5245ACC[8]
  • NM_005188.4:c.107ACC[8]MANE SELECT
  • NP_005179.2:p.His42dup
  • LRG_608:g.5245ACC[8]
  • NC_000011.9:g.119077232_119077233insCAC
  • NC_000011.9:g.119077234ACC[8]
  • NM_005188.2:c.125_127dupACC
  • NM_005188.2:c.127_128insACC
  • NM_005188.3:c.125_127dupACC
  • NM_005188.4:c.125_127dupMANE SELECT
  • c.127_128insACC
  • p.H42dup
Links:
dbSNP: rs373212940
NCBI 1000 Genomes Browser:
rs373212940
Molecular consequence:
  • NM_005188.4:c.107ACC[8] - inframe_insertion - [Sequence Ontology: SO:0001821]
Observations:
4

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000062022Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Likely benign
(Oct 31, 2014)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000224467Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions)
Likely benign
(May 19, 2015)
germlineclinical testing

Citation Link,

SCV000593861Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Benign
(Jan 4, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001362211Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Benign
(Dec 10, 2019)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided44not providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

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
See all PubMed Citations (12)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000062022.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (1)

Description

c.125_127dupACC in exon 1 of CBL: This variant is not expected to have clinical significance because it has been identified in 0.2% (13/6806) of European Americ an and 0.8% (27/3260) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs397507488). This variant is an in-frame duplication which adds an additional histidine residue (His) to a short repeat of 7 histidines. Additionally, the number of histidines is not co nserved across species.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not provided4not provided

From Eurofins Ntd Llc (ga), SCV000224467.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Genetic Services Laboratory, University of Chicago, SCV000593861.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362211.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

Variant summary: CBL c.125_127dupACC (p.His42dup) results in a in-frame duplication which adds an additional histidine residue to a short repeat of 7 histidines. The variant allele was found at a frequency of 0.002 in 151840 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4400 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 19, 2024