19-44780993-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_012116.4(CBLC):c.442A>G(p.Met148Val) 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 1,461,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CBLC NM_012116.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0220

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05804965).
• BP6: Variant 19-44780993-A-G is Benign according to our data. Variant chr19-44780993-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2270261.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLC	NM_012116.4	c.442A>G	p.Met148Val	missense_variant	2/11	ENST00000647358.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLC	ENST00000647358.2	c.442A>G	p.Met148Val	missense_variant	2/11		NM_012116.4	P1
CBLC	ENST00000341505.4	c.442A>G	p.Met148Val	missense_variant	2/10	1
CBLC	ENST00000647063.1	c.70A>G	p.Met24Val	missense_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461188 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726892

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.013
Dann	Benign	0.34
DEOGEN2	Benign	0.27	T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.023	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.69	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.60	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.35	T;T;.
Sift4G	Benign	0.30	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.083
MutPred		0.28		Loss of ubiquitination at K143 (P = 0.0828);Loss of ubiquitination at K143 (P = 0.0828);Loss of ubiquitination at K143 (P = 0.0828);
MVP		0.46
MPC		0.29
ClinPred		0.17	T
GERP RS		-5.3
Varity_R		0.082
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45284250;