chr7-51028139-C-A

Position:

• chr7-51028139-C-A

Variant summary

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

The NM_015198.5(COBL):​c.2957G>T​(p.Arg986Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R986C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COBL NM_015198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.471

Genes affected

COBL (HGNC:22199): (cordon-bleu WH2 repeat protein) This gene encodes a protein that contains WH2 domains (WASP, Wiskott-Aldrich syndrome protein, homology domain-2) that interact with actin. The encoded actin regulator protein is required for growth and assembly of brush border microvilli that play a role in maintaining intestinal homeostasis. A similar protein in mouse functions in midbrain neural tube closure. A pseudogene of this gene is located on chromosome X. [provided by RefSeq, Oct 2016]

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=0.058909684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COBL	NM_015198.5	c.2957G>T	p.Arg986Leu	missense_variant	10/13	ENST00000265136.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COBL	ENST00000265136.12	c.2957G>T	p.Arg986Leu	missense_variant	10/13	1	NM_015198.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 07, 2023

The c.2957G>T (p.R986L) alteration is located in exon 10 (coding exon 10) of the COBL gene. This alteration results from a G to T substitution at nucleotide position 2957, causing the arginine (R) at amino acid position 986 to be replaced by a leucine (L). 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	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.18
DANN	Benign	0.90
DEOGEN2	Benign	0.040	T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;.;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.15	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Benign	0.046
Sift	Benign	0.035	D;D;D;.
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.56, 0.028	.;.;P;B
Vest4		0.10, 0.15
MutPred		0.29		.;.;Loss of loop (P = 0.0022);.;
MVP		0.16
MPC		0.071
ClinPred		0.12	T
GERP RS		-7.0
Varity_R		0.040
gMVP		0.20

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: chr7-51095836;