chr3-195342478-A-C

Position:

• chr3-195342478-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000326793.11(ACAP2):​c.521T>G​(p.Val174Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACAP2 ENST00000326793.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

ACAP2 (HGNC:16469): (ArfGAP with coiled-coil, ankyrin repeat and PH domains 2) Enables GTPase activator activity. Acts upstream of or within actin filament-based process. Located in ruffle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAP2	NM_012287.6	c.521T>G	p.Val174Gly	missense_variant	6/23	ENST00000326793.11	NP_036419.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAP2	ENST00000326793.11	c.521T>G	p.Val174Gly	missense_variant	6/23	1	NM_012287.6	ENSP00000324287	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000419 AC: 1 AN: 238662 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448588 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2023

The c.521T>G (p.V174G) alteration is located in exon 6 (coding exon 6) of the ACAP2 gene. This alteration results from a T to G substitution at nucleotide position 521, causing the valine (V) at amino acid position 174 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	D;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.70
MutPred		0.44		Loss of stability (P = 0.0012);.;Loss of stability (P = 0.0012);
MVP		0.85
MPC		1.7
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.82
gMVP		0.83

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: rs1362742677; hg19: chr3-195063207;