chr11-119206522-G-GCAC

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-7 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -7 classification points (ACMG Germline Pathogenicity v2019). PM4_SupportingBS2BP6_Strong

The NM_005188.4(CBL):c.125_127dupACC (p.His42dup) variant causes a disruptive inframe insertion change. The variant results in an in-frame change. The variant allele was found at a cumulative frequency of 0.00149 (AC=2,312) in the gnomAD database across 1,556,494 control chromosomes, including 5 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00942. Variant has been reported in ClinVar as Benign/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:14
• Conservation: PhyloP100: 1.04
• Publications: 4 publications found

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]

CBL Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM4Protein length change in non-repeat region		Single amino-acid in-frame indel in non-repetitive region — protein length change, supporting (PM4 +1); In-frame indel in non-repetitive region — protein length change (1 AA).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (14/14 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 5.; Very high cumulative gnomAD AC = 2312 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005188.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CBL NM_005188.4	MANE Select	c.125_127dupACC p.His42dup	disruptive_inframe_insertion	Exon 1 of 16	Prot: NP_005179.2

CBL NM_005188.4

MANE Select

HGVSc / HGVSpc.125_127dupACCp.His42dup

Exon rankExon 1 of 16

disruptive_inframe_insertion

Prot: NP_005179.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CBL ENST00000264033.6	TSL:1MANE Select	c.125_127dupACC p.His42dup	disruptive_inframe_insertion	Exon 1 of 16	Prot: ENSP00000264033.3 UniProt:
	CBL ENST00000634586.1	TSL:5	c.125_127dupACC p.His42dup	disruptive_inframe_insertion	Exon 1 of 18	Prot: ENSP00000489218.1 UniProt:
	CBL ENST00000637974.1	TSL:5	c.119_121dupACC p.His40dup	disruptive_inframe_insertion	Exon 1 of 17	Prot: ENSP00000490763.1 UniProt:

CBL ENST00000264033.6

TSL:1MANE Select

HGVSc / HGVSpc.125_127dupACCp.His42dup

Exon rankExon 1 of 16

disruptive_inframe_insertion

Prot: ENSP00000264033.3UniProt: P22681

CBL ENST00000634586.1

TSL:5

HGVSc / HGVSpc.125_127dupACCp.His42dup

Exon rankExon 1 of 18

disruptive_inframe_insertion

Prot: ENSP00000489218.1UniProt: A0A0U1RQX8

CBL ENST00000637974.1

TSL:5

HGVSc / HGVSpc.119_121dupACCp.His40dup

Exon rankExon 1 of 17

disruptive_inframe_insertion

Prot: ENSP00000490763.1UniProt: A0A1B0GW38

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00361	AC:548	Hom:3	AN:151854	Cov:32
GnomAD2 exomes	AF: 0.00198	AC:301	Hom:	AN:151840	Cov:
GnomAD4 exome	AF: 0.00126	AC:1764	Hom:2	AN:1404532	Cov:32
GnomAD4 genome	AF: 0.00361	AC:548	Hom:3	AN:151962	Cov:32
TOPMed (Bravo) Warning	AF: 0.00367	AC:972	Hom:3	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00120	AC:40	Hom:0	AN:33382	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.00397	AC:40	Hom:	AN:10066	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00173	AC:207	Hom:0	AN:119884	Cov:
Turkish Variome	AF: 0.00208	AC:12	Hom:0	AN:5774	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00313	AC:28	Hom:0	AN:8960	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000387	11	28408	0.000971	28	28826
SCHEMA(Schizophrenia)	0.00339	77	22698	0.00165	48	29176

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	CBL-related disorder (1)
-	-	1	Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	RASopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	55/45	polymorphism
PhyloP100	Benign	1.0

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs373212940;

hg19: chr11-119077232;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar