6-17421593-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006366.3(CAP2):c.38G>A(p.Arg13Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CAP2 NM_006366.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.230

Genes affected

CAP2 (HGNC:20039): (cyclase associated actin cytoskeleton regulatory protein 2) This gene was identified by its similarity to the gene for human adenylyl cyclase-associated protein. The function of the protein encoded by this gene is unknown. However, the protein appears to be able to interact with adenylyl cyclase-associated protein and actin. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0098593235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAP2	NM_006366.3	c.38G>A	p.Arg13Gln	missense_variant	2/13	ENST00000229922.7
CAP2	NM_001363534.2	c.38G>A	p.Arg13Gln	missense_variant	2/12
CAP2	NM_001363533.2	c.38G>A	p.Arg13Gln	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAP2	ENST00000229922.7	c.38G>A	p.Arg13Gln	missense_variant	2/13	1	NM_006366.3	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251492 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135922

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: 0.00333

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000197 AC: 288 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 130 AN XY: 727228

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: 0.00359

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy, dilated, 2I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Program, Stanford Medicine

Jun 07, 2021

The p.Arg13Gln variant in the CAP2 gene has not been previously reported in association with disease. This variant has been identified in 82/25,122 Finnish chromosomes (110/282,866 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a frequency high enough to rule out pathogenicity. The arginine at position 13 is not evolutionarily conserved and several mammalian species have a glutamine at this position. Computational tools predict that the p.Arg13Gln does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg13Gln variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	6.7
Dann	Benign	0.94
DEOGEN2	Benign	0.016	T;T;.;T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Uncertain	0.91	D;D;D;T;D;T;D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.64	N;.;.;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.98	N;.;.;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.17	T;.;.;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T;T;T
Polyphen		0.010	B;.;.;B;B;.;.
Vest4		0.23
MVP		0.20
MPC		0.28
ClinPred		0.020	T
GERP RS		-7.4
Varity_R		0.031
gMVP		0.25

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: rs201044058; hg19: chr6-17421824;