11-119206522-GCACCACCACCAC-GCACCACCACCACCAC

Variant names:

• chr11-119206522-G-GCAC
• rs373212940
• NM_005188.4:c.125_127dupACC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005188.4(CBL):​c.125_127dupACC​(p.His42dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,556,494 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CBL NM_005188.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.04

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 11-119206522-G-GCAC is Benign according to our data. Variant chr11-119206522-G-GCAC is described in ClinVar as [Likely_benign]. Clinvar id is 40400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00361 (548/151962) while in subpopulation AFR AF= 0.0102 (424/41474). AF 95% confidence interval is 0.00942. There are 3 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 548 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.125_127dupACC	p.His42dup	disruptive_inframe_insertion	Exon 1 of 16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.125_127dupACC	p.His42dup	disruptive_inframe_insertion	Exon 1 of 16	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 548 AN: 151854 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.000604

Gnomad OTH AF: 0.00433

GnomAD3 exomes AF: 0.00198 AC: 301 AN: 151840 Hom.: 1 AF XY: 0.00178 AC XY: 144 AN XY: 81094

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.00429

Gnomad SAS exome AF: 0.00295

Gnomad FIN exome AF: 0.000222

Gnomad NFE exome AF: 0.000552

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00126 AC: 1764 AN: 1404532 Hom.: 2 Cov.: 32 AF XY: 0.00123 AC XY: 853 AN XY: 693478

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00308

Gnomad4 SAS exome AF: 0.00280

Gnomad4 FIN exome AF: 0.000104

Gnomad4 NFE exome AF: 0.000818

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00361 AC: 548 AN: 151962 Hom.: 3 Cov.: 32 AF XY: 0.00347 AC XY: 258 AN XY: 74292

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000604

Gnomad4 OTH AF: 0.00428

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CBL: BS1, BS2 -

not specified Benign:4

Oct 31, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 04, 2022

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 19, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder Benign:1

Dec 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan-like syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CBL-related disorder Benign:1

May 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Dec 20, 2021

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Dec 08, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373212940; hg19: chr11-119077232;