rs2510152

Variant names:

• chr11-119277863-G-T
• rs2510152
• NM_005188.4:c.1095+19G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-119277863-G-T
• chr11-119277863-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005188.4(CBL):​c.1095+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,511,976 control chromosomes in the GnomAD database, including 252,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (31059 hom., cov: 32)
  • Exomes 𝑓: 0.56 (221064 hom.)
• Consequence: CBL NM_005188.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.253
• Publications: 22 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 (BayesDel_noAF=-0.86).
• BP6: Variant 11-119277863-G-T is Benign according to our data. Variant chr11-119277863-G-T is described in ClinVar as Benign. ClinVar VariationId is 55796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

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.1095+19G>T		intron	N/A	NP_005179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.1095+19G>T		intron	N/A	ENSP00000264033.3	P22681
	CBL	ENST00000634586.1	TSL:5	c.1095+19G>T		intron	N/A	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000637974.1	TSL:5	c.1089+19G>T		intron	N/A	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94692 AN: 151898 Hom.: 31011 Cov.: 32

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.598

GnomAD2 exomes AF: 0.588 AC: 147500 AN: 250970 AF XY: 0.597

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.881

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.536

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.562 AC: 764680 AN: 1359960 Hom.: 221064 Cov.: 22 AF XY: 0.568 AC XY: 387726 AN XY: 682430

African (AFR) AF: 0.813 AC: 25616 AN: 31504

American (AMR) AF: 0.370 AC: 16511 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 16696 AN: 25524

East Asian (EAS) AF: 0.865 AC: 33941 AN: 39232

South Asian (SAS) AF: 0.747 AC: 62932 AN: 84230

European-Finnish (FIN) AF: 0.557 AC: 29726 AN: 53362

Middle Eastern (MID) AF: 0.612 AC: 3409 AN: 5570

European-Non Finnish (NFE) AF: 0.532 AC: 542112 AN: 1018892

Other (OTH) AF: 0.591 AC: 33737 AN: 57064

GnomAD4 genome AF: 0.624 AC: 94794 AN: 152016 Hom.: 31059 Cov.: 32 AF XY: 0.628 AC XY: 46633 AN XY: 74290

African (AFR) AF: 0.803 AC: 33306 AN: 41480

American (AMR) AF: 0.463 AC: 7069 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2223 AN: 3470

East Asian (EAS) AF: 0.877 AC: 4525 AN: 5160

South Asian (SAS) AF: 0.762 AC: 3672 AN: 4820

European-Finnish (FIN) AF: 0.568 AC: 5984 AN: 10532

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.532 AC: 36144 AN: 67958

Other (OTH) AF: 0.600 AC: 1270 AN: 2116

Alfa AF: 0.570 Hom.: 21587

Bravo AF: 0.622

Asia WGS AF: 0.803 AC: 2794 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	CBL-related disorder (2)
-	-	2	not provided (3)
-	-	2	RASopathy (2)
-	-	1	Juvenile myelomonocytic leukemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.41
DANN	Benign	0.31
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs2510152; hg19: chr11-119148573; COSMIC: COSV50630143;