rs17122769

Variant names:

• chr11-119299770-G-A
• rs17122769
• NM_005188.4:c.2710G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005188.4(CBL):​c.2710G>A​(p.Val904Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000823 in 1,614,104 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 2.71
• Publications: 11 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• juvenile myelomonocytic leukemia

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060166717).
• BP6: Variant 11-119299770-G-A is Benign according to our data. Variant chr11-119299770-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133813.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 = 0.00422 (642/152292) while in subpopulation AFR AF = 0.0147 (609/41558). AF 95% confidence interval is 0.0137. There are 5 homozygotes in GnomAd4. There are 283 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 642 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.2710G>A	p.Val904Ile	missense	Exon 16 of 16	NP_005179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.2710G>A	p.Val904Ile	missense	Exon 16 of 16	ENSP00000264033.3	P22681
	CBL	ENST00000634840.1	TSL:5	c.2578G>A	p.Val860Ile	missense	Exon 15 of 15	ENSP00000489324.1	A0A0U1RR39
	CBL	ENST00000634586.1	TSL:5	c.2575+135G>A		intron	N/A	ENSP00000489218.1	A0A0U1RQX8

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 643 AN: 152174 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.000118

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00119 AC: 300 AN: 251306 AF XY: 0.000861

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000470 AC: 687 AN: 1461812 Hom.: 2 Cov.: 31 AF XY: 0.000419 AC XY: 305 AN XY: 727210

African (AFR) AF: 0.0140 AC: 470 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1111994

Other (OTH) AF: 0.000762 AC: 46 AN: 60392

GnomAD4 genome AF: 0.00422 AC: 642 AN: 152292 Hom.: 5 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74452

African (AFR) AF: 0.0147 AC: 609 AN: 41558

American (AMR) AF: 0.00144 AC: 22 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00186 Hom.: 3

Bravo AF: 0.00488

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00141 AC: 171

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	CBL-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Juvenile myelomonocytic leukemia (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.51	N
PhyloP100		2.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.23
Sift	Benign	0.36	T
Sift4G	Benign	0.67	T
Polyphen		0.0050	B
Vest4		0.14
MVP		0.78
MPC		0.17
ClinPred		0.0092	T
GERP RS		4.9
Varity_R		0.055
gMVP		0.12
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17122769; hg19: chr11-119170480;