2-85394936-T-C

Variant names:

• chr2-85394936-T-C
• rs6886
• NM_001747.4:c.1004A>G

Variant summary

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

The NM_001747.4(CAPG):​c.1004A>G​(p.His335Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,610,230 control chromosomes in the GnomAD database, including 329,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.64 (31666 hom., cov: 32)
  • Exomes 𝑓: 0.63 (297766 hom.)
• Consequence: CAPG NM_001747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 54 publications found

Genes affected

CAPG (HGNC:1474): (capping actin protein, gelsolin like) This gene encodes a member of the gelsolin/villin family of actin-regulatory proteins. The encoded protein reversibly blocks the barbed ends of F-actin filaments in a Ca2+ and phosphoinositide-regulated manner, but does not sever preformed actin filaments. By capping the barbed ends of actin filaments, the encoded protein contributes to the control of actin-based motility in non-muscle cells. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7096057E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001747.4. 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
	CAPG	NM_001747.4	MANE Select	c.1004A>G	p.His335Arg	missense	Exon 10 of 10	NP_001738.2	P40121-1
	CAPG	NM_001256139.2		c.1004A>G	p.His335Arg	missense	Exon 10 of 10	NP_001243068.1	P40121-1
	CAPG	NM_001320732.2		c.1004A>G	p.His335Arg	missense	Exon 10 of 10	NP_001307661.1	P40121-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPG	ENST00000263867.9	TSL:1 MANE Select	c.1004A>G	p.His335Arg	missense	Exon 10 of 10	ENSP00000263867.4	P40121-1
	CAPG	ENST00000409724.5	TSL:1	c.1004A>G	p.His335Arg	missense	Exon 10 of 10	ENSP00000386965.1	P40121-1
	CAPG	ENST00000409921.5	TSL:1	c.959A>G	p.His320Arg	missense	Exon 10 of 10	ENSP00000387063.1	P40121-2

Frequencies

GnomAD3 genomes AF: 0.639 AC: 97122 AN: 151890 Hom.: 31621 Cov.: 32

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.526

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.619

GnomAD2 exomes AF: 0.576 AC: 144530 AN: 251052 AF XY: 0.579

Gnomad AFR exome AF: 0.729

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.483

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.646

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.634 AC: 924871 AN: 1458222 Hom.: 297766 Cov.: 37 AF XY: 0.631 AC XY: 457755 AN XY: 725682

African (AFR) AF: 0.730 AC: 24387 AN: 33400

American (AMR) AF: 0.374 AC: 16707 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13586 AN: 26104

East Asian (EAS) AF: 0.510 AC: 20235 AN: 39676

South Asian (SAS) AF: 0.532 AC: 45846 AN: 86192

European-Finnish (FIN) AF: 0.610 AC: 32564 AN: 53412

Middle Eastern (MID) AF: 0.559 AC: 3221 AN: 5764

European-Non Finnish (NFE) AF: 0.659 AC: 731135 AN: 1108724

Other (OTH) AF: 0.617 AC: 37190 AN: 60278

GnomAD4 genome AF: 0.639 AC: 97207 AN: 152008 Hom.: 31666 Cov.: 32 AF XY: 0.631 AC XY: 46892 AN XY: 74276

African (AFR) AF: 0.731 AC: 30299 AN: 41450

American (AMR) AF: 0.494 AC: 7549 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1772 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2476 AN: 5160

South Asian (SAS) AF: 0.526 AC: 2531 AN: 4810

European-Finnish (FIN) AF: 0.613 AC: 6486 AN: 10576

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44084 AN: 67960

Other (OTH) AF: 0.620 AC: 1311 AN: 2114

Alfa AF: 0.633 Hom.: 98732

Bravo AF: 0.630

TwinsUK AF: 0.658 AC: 2441

ALSPAC AF: 0.662 AC: 2553

ESP6500AA AF: 0.733 AC: 3228

ESP6500EA AF: 0.645 AC: 5543

ExAC AF: 0.588 AC: 71331

Asia WGS AF: 0.513 AC: 1784 AN: 3478

EpiCase AF: 0.633

EpiControl AF: 0.644

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.000017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.045	N
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.049
Sift	Benign	0.48	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.16
ClinPred		0.0021	T
GERP RS		3.9
Varity_R		0.059
gMVP		0.18
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6886; hg19: chr2-85622059; COSMIC: COSV105849004; COSMIC: COSV105849004;