rs373212940

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM2PM4

The NM_005188.4(CBL):c.116_127delACCACCACCACC (p.His39_His42del) variant causes a disruptive inframe deletion change. The variant results in an in-frame change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is present but has an allele frequency of zero in the gnomAD population database. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CBL
NM_005188.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.31

Publications

4 publications found

Variant links:

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

CBL links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005188.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 points.

PM2

Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.

PM4

In-frame indel in non-repetitive region — protein length change (PM4); In-frame indel in non-repetitive region — protein length change (4 AA).

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.116_127delACCACCACCACC	p.His39_His42del	disruptive_inframe_deletion	Exon 1 of 16	NP_005179.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBL	ENST00000264033.6	TSL:1 MANE Select	c.116_127delACCACCACCACC	p.His39_His42del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000264033.3	P22681
CBL	ENST00000634586.1	TSL:5	c.116_127delACCACCACCACC	p.His39_His42del	disruptive_inframe_deletion	Exon 1 of 18	ENSP00000489218.1	A0A0U1RQX8
CBL	ENST00000637974.1	TSL:5	c.110_121delACCACCACCACC	p.His37_His40del	disruptive_inframe_deletion	Exon 1 of 17	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000132

AC:

AN:

151840

AF XY:

0.0000247

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1404554

Hom.:

AF XY:

0.00000433

AC XY:

AN XY:

693486

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32128

American (AMR)

AF:

0.00

AC:

AN:

36158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25202

East Asian (EAS)

AF:

0.00

AC:

AN:

36668

South Asian (SAS)

AF:

0.0000250

AC:

AN:

79920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1082936

Other (OTH)

AF:

0.00

AC:

AN:

58246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.3

Mutation Taster

=49/151

disease causing

(source)

Splicing

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over