rs397517078

Variant names:

• chr11-119278498-C-CT
• rs397517078
• NM_005188.4:c.1228-10dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005188.4(CBL):​c.1228-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,610,996 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: CBL NM_005188.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics, ClinGen, G2P
• 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 -16 ACMG points.

• BP6: Variant 11-119278498-C-CT is Benign according to our data. Variant chr11-119278498-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000374 (57/152262) while in subpopulation EAS AF = 0.00598 (31/5182). AF 95% confidence interval is 0.00433. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 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.1228-10dupT		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.1228-12_1228-11insT		intron	N/A	ENSP00000264033.3	P22681
	CBL	ENST00000634586.1	TSL:5	c.1228-12_1228-11insT		intron	N/A	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000637974.1	TSL:5	c.1222-12_1222-11insT		intron	N/A	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00597

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000951 AC: 239 AN: 251332 AF XY: 0.000780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00799

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000255 AC: 372 AN: 1458734 Hom.: 2 Cov.: 32 AF XY: 0.000238 AC XY: 173 AN XY: 725922

African (AFR) AF: 0.0000599 AC: 2 AN: 33414

American (AMR) AF: 0.00262 AC: 117 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00587 AC: 233 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109140

Other (OTH) AF: 0.000249 AC: 15 AN: 60266

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74454

African (AFR) AF: 0.0000722 AC: 3 AN: 41540

American (AMR) AF: 0.00137 AC: 21 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000559

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397517078;

hg19: chr11-119149208;