19-44792389-C-G

Variant names:

• chr19-44792389-C-G
• rs758907585
• NM_012116.4:c.1012C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012116.4(CBLC):​c.1012C>G​(p.Leu338Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CBLC NM_012116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4013946).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012116.4. 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
	CBLC	NM_012116.4	MANE Select	c.1012C>G	p.Leu338Val	missense	Exon 7 of 11	NP_036248.3
	CBLC	NM_001130852.1		c.874C>G	p.Leu292Val	missense	Exon 6 of 10	NP_001124324.1	Q9ULV8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLC	ENST00000647358.2	MANE Select	c.1012C>G	p.Leu338Val	missense	Exon 7 of 11	ENSP00000494162.1	Q9ULV8-1
	CBLC	ENST00000341505.4	TSL:1	c.874C>G	p.Leu292Val	missense	Exon 6 of 10	ENSP00000340250.4	Q9ULV8-2
	CBLC	ENST00000880089.1		c.1012C>G	p.Leu338Val	missense	Exon 7 of 12	ENSP00000550148.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250948 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461268 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726958

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.36
Sift	Benign	0.062	T
Sift4G	Benign	0.063	T
Polyphen		0.95	P
Vest4		0.52
MutPred		0.47		Loss of helix (P = 0.1706)
MVP		0.91
MPC		0.71
ClinPred		0.73	D
GERP RS		2.8
Varity_R		0.048
gMVP		0.29
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs758907585; hg19: chr19-45295646;