rs6886

Positions:

• chr2-85394936-T-A
• chr2-85394936-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001747.4(CAPG):​c.1004A>T​(p.His335Leu) 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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H335R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPG NM_001747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30330732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPG	NM_001747.4	c.1004A>T	p.His335Leu	missense_variant	10/10	ENST00000263867.9	NP_001738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPG	ENST00000263867.9	c.1004A>T	p.His335Leu	missense_variant	10/10	1	NM_001747.4	ENSP00000263867	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T;T;.;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	.;T;T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.93	L;.;.;L;L
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.054
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.0030	B;.;.;B;B
Vest4		0.15
MutPred		0.56		Loss of disorder (P = 0.0676);.;.;Loss of disorder (P = 0.0676);Loss of disorder (P = 0.0676);
MVP		0.45
MPC		0.17
ClinPred		0.65	D
GERP RS		3.9
Varity_R		0.12
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6886; hg19: chr2-85622059;