3-195292434-G-A

Position:

• chr3-195292434-G-A

Variant summary

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

The NM_012287.6(ACAP2):​c.1784C>T​(p.Ser595Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S595Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAP2 NM_012287.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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=0.24303609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAP2	NM_012287.6	c.1784C>T	p.Ser595Phe	missense_variant	19/23	ENST00000326793.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAP2	ENST00000326793.11	c.1784C>T	p.Ser595Phe	missense_variant	19/23	1	NM_012287.6	P1
ACAP2	ENST00000450200.2	c.1889C>T	p.Ser630Phe	missense_variant	20/23	5
ACAP2	ENST00000466876.2	c.110C>T	p.Ser37Phe	missense_variant	2/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 16, 2021

The c.1784C>T (p.S595F) alteration is located in exon 19 (coding exon 19) of the ACAP2 gene. This alteration results from a C to T substitution at nucleotide position 1784, causing the serine (S) at amino acid position 595 to be replaced by a phenylalanine (F). 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	0.091
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.13
Sift	Benign	0.056	T;.
Sift4G	Benign	0.064	T;T
Polyphen		0.52	P;.
Vest4		0.42
MutPred		0.37		Gain of glycosylation at S595 (P = 0.007);.;
MVP		0.74
MPC		0.76
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.24

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-195013163;