19-44800412-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012116.4(CBLC):c.1394C>T(p.Ala465Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CBLC NM_012116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.535

Genes affected

CBLC (HGNC:15961): (Cbl proto-oncogene C) This gene encodes a member of the Cbl family of E3 ubiquitin ligases. Cbl proteins play important roles in cell signaling through the ubiquitination and subsequent downregulation of tyrosine kinases. Expression of this gene may be restricted to epithelial cells, and alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06068489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLC	NM_012116.4	c.1394C>T	p.Ala465Val	missense_variant	10/11	ENST00000647358.2
CBLC	NM_001130852.1	c.1256C>T	p.Ala419Val	missense_variant	9/10
CBLC	XM_011526689.3			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLC	ENST00000647358.2	c.1394C>T	p.Ala465Val	missense_variant	10/11		NM_012116.4	P1
CBLC	ENST00000341505.4	c.1256C>T	p.Ala419Val	missense_variant	9/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460990 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1394C>T (p.A465V) alteration is located in exon 10 (coding exon 10) of the CBLC gene. This alteration results from a C to T substitution at nucleotide position 1394, causing the alanine (A) at amino acid position 465 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0082	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N;N;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.11	T;T;.
Polyphen		0.013	B;B;B
Vest4		0.17
MutPred		0.056		Loss of glycosylation at P463 (P = 0.0809);.;Loss of glycosylation at P463 (P = 0.0809);
MVP		0.79
MPC		0.93
ClinPred		0.32	T
GERP RS		-0.42
Varity_R		0.052
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs904426529; hg19: chr19-45303669; COSMIC: COSV54322276; COSMIC: COSV54322276;