11-119206522-GCACCACCACCAC-GCACCAC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_005188.4(CBL):c.122_127delACCACC(p.His41_His42del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000173 in 1,556,370 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H41H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Consequence

CBL
NM_005188.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.30

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, Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
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

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005188.4

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000988 (15/151854) while in subpopulation AMR AF = 0.000852 (13/15264). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.122_127delACCACC	p.His41_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.122_127delACCACC	p.His41_His42del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000264033.3	P22681
CBL	ENST00000634586.1	TSL:5	c.122_127delACCACC	p.His41_His42del	disruptive_inframe_deletion	Exon 1 of 18	ENSP00000489218.1	A0A0U1RQX8
CBL	ENST00000637974.1	TSL:5	c.116_121delACCACC	p.His39_His40del	disruptive_inframe_deletion	Exon 1 of 17	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000461

AC:

AN:

151840

AF XY:

0.0000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

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:

0.00000854

AC:

AN:

1404516

Hom.:

AF XY:

0.0000144

AC XY:

AN XY:

693468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32122

American (AMR)

AF:

0.000194

AC:

AN:

36158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25200

East Asian (EAS)

AF:

0.00

AC:

AN:

36666

South Asian (SAS)

AF:

0.00

AC:

AN:

79918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.00000369

AC:

AN:

1082920

Other (OTH)

AF:

0.0000172

AC:

AN:

58244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151854

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41354

American (AMR)

AF:

0.000852

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67904

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000718

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Mutation Taster

=125/75

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over