chr6-17421593-G-A

Variant names:

• chr6-17421593-G-A
• rs201044058
• NM_006366.3:c.38G>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 rank	MANE	Protein	UniProt
CAP2	NM_006366.3	c.38G>A	p.Arg13Gln	missense_variant	Exon 2 of 13	ENST00000229922.7	NP_006357.1
CAP2	NM_001363534.2	c.38G>A	p.Arg13Gln	missense_variant	Exon 2 of 12		NP_001350463.1
CAP2	NM_001363533.2	c.38G>A	p.Arg13Gln	missense_variant	Exon 2 of 10		NP_001350462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAP2	ENST00000229922.7	c.38G>A	p.Arg13Gln	missense_variant	Exon 2 of 13	1	NM_006366.3	ENSP00000229922.2

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

Jun 07, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;