7-51026650-C-T

Variant names:

• chr7-51026650-C-T
• rs777875725
• NM_015198.5:c.3400G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015198.5(COBL):​c.3400G>A​(p.Gly1134Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: COBL NM_015198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.45
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03780374).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015198.5. 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
	COBL	NM_015198.5	MANE Select	c.3400G>A	p.Gly1134Arg	missense	Exon 11 of 13	NP_056013.2
	COBL	NM_001410881.1		c.3646G>A	p.Gly1216Arg	missense	Exon 13 of 15	NP_001397810.1	O75128-2
	COBL	NM_001287436.3		c.3571G>A	p.Gly1191Arg	missense	Exon 12 of 14	NP_001274365.1	O75128-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COBL	ENST00000265136.12	TSL:1 MANE Select	c.3400G>A	p.Gly1134Arg	missense	Exon 11 of 13	ENSP00000265136.7	O75128-1
	COBL	ENST00000431948.6	TSL:1	c.3646G>A	p.Gly1216Arg	missense	Exon 13 of 15	ENSP00000413498.2	O75128-2
	COBL	ENST00000395542.6	TSL:1	c.3571G>A	p.Gly1191Arg	missense	Exon 12 of 14	ENSP00000378912.3	O75128-7

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251154 AF XY: 0.000169

Gnomad AFR exome AF: 0.0000615

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: 0.000326

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 176 AN XY: 727120

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000344 AC: 383 AN: 1111948

Other (OTH) AF: 0.000116 AC: 7 AN: 60392

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

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	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.024
DANN	Benign	0.67
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.043
Sift	Benign	0.36	T
Sift4G	Benign	0.48	T
Polyphen		0.75	P
Vest4		0.23
MutPred		0.16		Loss of loop (P = 0.0073)
MVP		0.46
MPC		0.11
ClinPred		0.030	T
GERP RS		-9.9
Varity_R		0.041
gMVP		0.098
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs777875725; hg19: chr7-51094347; COSMIC: COSV54347085; COSMIC: COSV54347085;