rs2240089

Variant names:

• chr7-51028339-G-C
• rs2240089
• NM_015198.5:c.2757C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000265136.12(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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2198 hom., cov: 34)
  • Exomes 𝑓: 0.17 (22847 hom.)
• Consequence: COBL ENST00000265136.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265136.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COBL	NM_015198.5	MANE Select	c.2757C>G	p.His919Gln	missense	Exon 10 of 13	NP_056013.2
	COBL	NM_001410881.1		c.3003C>G	p.His1001Gln	missense	Exon 12 of 15	NP_001397810.1
	COBL	NM_001287436.3		c.2928C>G	p.His976Gln	missense	Exon 11 of 14	NP_001274365.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COBL	ENST00000265136.12	TSL:1 MANE Select	c.2757C>G	p.His919Gln	missense	Exon 10 of 13	ENSP00000265136.7
	COBL	ENST00000431948.6	TSL:1	c.3003C>G	p.His1001Gln	missense	Exon 12 of 15	ENSP00000413498.2
	COBL	ENST00000395542.6	TSL:1	c.2928C>G	p.His976Gln	missense	Exon 11 of 14	ENSP00000378912.3

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

GnomAD2 exomes AF: 0.183 AC: 46106 AN: 251432 AF XY: 0.188

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 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

African (AFR) AF: 0.113 AC: 3768 AN: 33480

American (AMR) AF: 0.164 AC: 7334 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6935 AN: 26136

East Asian (EAS) AF: 0.298 AC: 11821 AN: 39700

South Asian (SAS) AF: 0.237 AC: 20438 AN: 86254

European-Finnish (FIN) AF: 0.128 AC: 6818 AN: 53414

Middle Eastern (MID) AF: 0.224 AC: 1290 AN: 5768

European-Non Finnish (NFE) AF: 0.163 AC: 181423 AN: 1112002

Other (OTH) AF: 0.187 AC: 11310 AN: 60396

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

African (AFR) AF: 0.112 AC: 4650 AN: 41564

American (AMR) AF: 0.179 AC: 2743 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 957 AN: 3472

East Asian (EAS) AF: 0.302 AC: 1560 AN: 5160

South Asian (SAS) AF: 0.251 AC: 1212 AN: 4828

European-Finnish (FIN) AF: 0.126 AC: 1338 AN: 10606

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11221 AN: 68008

Other (OTH) AF: 0.199 AC: 420 AN: 2112

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 v4.9

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
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.11
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.18	T
Sift4G	Benign	0.30	T
Polyphen		0.45	P
Vest4		0.070
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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