NM_012287.6:c.2003A>C

Variant names:

• chr3-195291766-T-G
• rs763075303
• NM_012287.6:c.2003A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012287.6(ACAP2):​c.2003A>C​(p.Asn668Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. N668S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACAP2 NM_012287.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.48
• Publications: 0 publications found

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]

ENSG00000295476 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012287.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAP2	NM_012287.6	MANE Select	c.2003A>C	p.Asn668Thr	missense	Exon 20 of 23	NP_036419.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAP2	ENST00000326793.11	TSL:1 MANE Select	c.2003A>C	p.Asn668Thr	missense	Exon 20 of 23	ENSP00000324287.6	Q15057
	ACAP2	ENST00000867120.1		c.2192A>C	p.Asn731Thr	missense	Exon 22 of 25	ENSP00000537179.1
	ACAP2	ENST00000867114.1		c.2108A>C	p.Asn703Thr	missense	Exon 21 of 24	ENSP00000537173.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.66		Loss of disorder (P = 0.1581)
MVP		0.59
MPC		1.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.78
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763075303; hg19: chr3-195012495;