rs2240089

Positions:

• chr7-51028339-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015198.5(COBL):​c.2757C>G​(p.His919Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,614,138 control chromosomes in the GnomAD database, including 25,045 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2198 hom., cov: 34)
  • Exomes 𝑓: 0.17 (22847 hom.)
• Consequence: COBL NM_015198.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106

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]

COBL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058608055).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COBL	NM_015198.5	c.2757C>G	p.His919Gln	missense_variant	10/13	ENST00000265136.12	NP_056013.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COBL	ENST00000265136.12	c.2757C>G	p.His919Gln	missense_variant	10/13	1	NM_015198.5	ENSP00000265136.7

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24535 AN: 152146 Hom.: 2204 Cov.: 34

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.183 AC: 46106 AN: 251432 Hom.: 4715 AF XY: 0.188 AC XY: 25563 AN XY: 135884

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.299

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.172 AC: 251137 AN: 1461874 Hom.: 22847 Cov.: 35 AF XY: 0.175 AC XY: 127104 AN XY: 727242

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.161 AC: 24525 AN: 152264 Hom.: 2198 Cov.: 34 AF XY: 0.162 AC XY: 12051 AN XY: 74428

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.199

Alfa AF: 0.174 Hom.: 1872

Bravo AF: 0.163

TwinsUK AF: 0.171 AC: 635

ALSPAC AF: 0.169 AC: 653

ESP6500AA AF: 0.107 AC: 473

ESP6500EA AF: 0.174 AC: 1496

ExAC AF: 0.182 AC: 22108

Asia WGS AF: 0.258 AC: 894 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.184

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.74
DEOGEN2	Benign	0.025	T;T;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.0059	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;.;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.18	T;T;T;.
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.45, 0.40	.;.;P;B
Vest4		0.070, 0.055
MutPred		0.056		.;.;Loss of glycosylation at T915 (P = 0.1784);.;
MPC		0.085
ClinPred		0.0076	T
GERP RS		0.38
Varity_R		0.031
gMVP		0.17

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: rs2240089; hg19: chr7-51096036; COSMIC: COSV54337630; COSMIC: COSV54337630;