NM_005188.4:c.125_127dupACC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. L43L) has been classified 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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.04

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: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005188.4

BP6

Variant 11-119206522-G-GCAC is Benign according to our data. Variant chr11-119206522-G-GCAC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 548 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.125_127dupACC	p.His42dup	disruptive_inframe_insertion	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.125_127dupACC	p.His42dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000264033.3	P22681
CBL	ENST00000634586.1	TSL:5	c.125_127dupACC	p.His42dup	disruptive_inframe_insertion	Exon 1 of 18	ENSP00000489218.1	A0A0U1RQX8
CBL	ENST00000637974.1	TSL:5	c.119_121dupACC	p.His40dup	disruptive_inframe_insertion	Exon 1 of 17	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes

AF:

0.00361

AC:

548

AN:

151854

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00198

AC:

301

AN:

151840

AF XY:

0.00178

show subpopulations

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 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.:

Cov.:

AF XY:

0.00123

AC XY:

853

AN XY:

693478

show subpopulations

African (AFR)

AF:

0.0101

AC:

325

AN:

32126

American (AMR)

AF:

0.00144

AC:

AN:

36156

Ashkenazi Jewish (ASJ)

AF:

0.00139

AC:

AN:

25202

East Asian (EAS)

AF:

0.00308

AC:

113

AN:

36666

South Asian (SAS)

AF:

0.00280

AC:

224

AN:

79920

European-Finnish (FIN)

AF:

0.000104

AC:

AN:

47904

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.000818

AC:

886

AN:

1082922

Other (OTH)

AF:

0.00189

AC:

110

AN:

58246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

182

274

365

456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00361

AC:

548

AN:

151962

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

258

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0102

AC:

424

AN:

41474

American (AMR)

AF:

0.00170

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3460

East Asian (EAS)

AF:

0.00252

AC:

AN:

5156

South Asian (SAS)

AF:

0.00437

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000604

AC:

AN:

67894

Other (OTH)

AF:

0.00428

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000401

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Cardiovascular phenotype (1)

CBL-related disorder (1)

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder (1)

Noonan syndrome and Noonan-related syndrome (1)

Noonan-like syndrome (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=55/45

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