rs2229072

Variant names:

• chr11-119285022-G-A
• rs2229072
• NM_005188.4:c.1485G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-119285022-G-A
• chr11-119285022-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005188.4(CBL):​c.1485G>A​(p.Pro495Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,022 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P495P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (36 hom.)
• Consequence: CBL NM_005188.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.30
• Publications: 2 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, 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-119285022-G-A is Benign according to our data. Variant chr11-119285022-G-A is described in ClinVar as Benign. ClinVar VariationId is 45201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00561 (853/152142) while in subpopulation SAS AF = 0.016 (77/4824). AF 95% confidence interval is 0.0147. There are 8 homozygotes in GnomAd4. There are 422 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 853 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.1485G>A	p.Pro495Pro	synonymous	Exon 10 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.1485G>A	p.Pro495Pro	synonymous	Exon 10 of 16	ENSP00000264033.3	P22681
	CBL	ENST00000634586.1	TSL:5	c.1485G>A	p.Pro495Pro	synonymous	Exon 10 of 18	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000637974.1	TSL:5	c.1479G>A	p.Pro493Pro	synonymous	Exon 10 of 17	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152024 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00396 AC: 996 AN: 251470 AF XY: 0.00422

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00216 AC: 3159 AN: 1461880 Hom.: 36 Cov.: 33 AF XY: 0.00243 AC XY: 1767 AN XY: 727240

African (AFR) AF: 0.0178 AC: 596 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0156 AC: 1342 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53420

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.000841 AC: 935 AN: 1112002

Other (OTH) AF: 0.00338 AC: 204 AN: 60394

GnomAD4 genome AF: 0.00561 AC: 853 AN: 152142 Hom.: 8 Cov.: 32 AF XY: 0.00567 AC XY: 422 AN XY: 74368

African (AFR) AF: 0.0157 AC: 651 AN: 41496

American (AMR) AF: 0.00209 AC: 32 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4824

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 67994

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00615

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	CBL-related disorder (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
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.8
DANN	Benign	0.85
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229072; hg19: chr11-119155732; COSMIC: COSV50634231;