3-195320772-A-C

Variant names:

• chr3-195320772-A-C
• rs1020264470
• NM_012287.6:c.786T>G

Variant summary

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

The NM_012287.6(ACAP2):​c.786T>G​(p.Asp262Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,324 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACAP2 NM_012287.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2689098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAP2	NM_012287.6	c.786T>G	p.Asp262Glu	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.786T>G	p.Asp262Glu	missense_variant	Exon 10 of 23	1	NM_012287.6	ENSP00000324287.6
ACAP2	ENST00000450200.2	c.786T>G	p.Asp262Glu	missense_variant	Exon 10 of 23	5		ENSP00000412338.2
ACAP2	ENST00000635383.1	c.786T>G	p.Asp262Glu	missense_variant	Exon 10 of 18	5		ENSP00000489156.1
ACAP2	ENST00000439758.3	c.408T>G	p.Asp136Glu	missense_variant	Exon 6 of 10	4		ENSP00000413388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461324 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727008

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.786T>G (p.D262E) alteration is located in exon 10 (coding exon 10) of the ACAP2 gene. This alteration results from a T to G substitution at nucleotide position 786, causing the aspartic acid (D) at amino acid position 262 to be replaced by a glutamic acid (E). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T;T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N;.;.
REVEL	Benign	0.22
Sift	Benign	0.40	T;.;.
Sift4G	Benign	0.48	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.63
MutPred		0.37		Gain of glycosylation at Y259 (P = 0.0312);.;Gain of glycosylation at Y259 (P = 0.0312);
MVP		0.60
MPC		0.67
ClinPred		0.78	D
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
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: rs1020264470; hg19: chr3-195041501;