3-195320764-T-C

Variant names:

• chr3-195320764-T-C
• rs1415745453
• NM_012287.6:c.794A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012287.6(ACAP2):​c.794A>G​(p.Asn265Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACAP2 NM_012287.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13314405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAP2	NM_012287.6	c.794A>G	p.Asn265Ser	missense_variant	Exon 10 of 23	ENST00000326793.11	NP_036419.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAP2	ENST00000326793.11	c.794A>G	p.Asn265Ser	missense_variant	Exon 10 of 23	1	NM_012287.6	ENSP00000324287.6
ACAP2	ENST00000450200.2	c.794A>G	p.Asn265Ser	missense_variant	Exon 10 of 23	5		ENSP00000412338.2
ACAP2	ENST00000635383.1	c.794A>G	p.Asn265Ser	missense_variant	Exon 10 of 18	5		ENSP00000489156.1
ACAP2	ENST00000439758.3	c.416A>G	p.Asn139Ser	missense_variant	Exon 6 of 10	4		ENSP00000413388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461346 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727022

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.794A>G (p.N265S) alteration is located in exon 10 (coding exon 10) of the ACAP2 gene. This alteration results from a A to G substitution at nucleotide position 794, causing the asparagine (N) at amino acid position 265 to be replaced by a serine (S). 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	Benign	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Uncertain	23
DANN	Benign	0.84
DEOGEN2	Benign	0.055	T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.10
Sift	Benign	0.43	T;.;.
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.35
MutPred		0.39		Gain of disorder (P = 0.1067);.;Gain of disorder (P = 0.1067);
MVP		0.36
MPC		0.51
ClinPred		0.52	D
GERP RS		3.5
Varity_R		0.061
gMVP		0.40

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: rs1415745453; hg19: chr3-195041493;