Genetic Variant CAP1:p.Val8Ile (chr1-40059368-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006367.4(CAP1):c.22G>A(p.Val8Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAP1
NM_006367.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.60

Variant links:

Genes affected

CAP1 (HGNC:20040): (cyclase associated actin cytoskeleton regulatory protein 1) The protein encoded by this gene is related to the S. cerevisiae CAP protein, which is involved in the cyclic AMP pathway. The human protein is able to interact with other molecules of the same protein, as well as with CAP2 and actin. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2016]

CAP1 links:

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ACMG classification

Classification made for transcript

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=0.33968222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAP1	NM_006367.4 link	c.22G>A	p.Val8Ile	missense_variant	Exon 2 of 13	ENST00000372805.8	NP_006358.2	Q01518-1D3DPU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAP1	ENST00000372805.8 link	c.22G>A	p.Val8Ile	missense_variant	Exon 2 of 13	1	NM_006367.4	ENSP00000361891.3		Q01518-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1460578

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22G>A (p.V8I) alteration is located in exon 2 (coding exon 1) of the CAP1 gene. This alteration results from a G to A substitution at nucleotide position 22, causing the valine (V) at amino acid position 8 to be replaced by an isoleucine (I). 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

0.15

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

T;.;T;T;T;T;T;T;.;.;T;.;T;T;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

.;.;T;T;D;T;D;.;.;T;T;T;T;T;T;D

M_CAP

Benign

0.0049

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.70

N;N;.;.;.;.;.;N;N;N;N;.;.;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.36

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.076

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D

Sift4G

Benign

0.50

T;T;T;T;D;T;T;T;T;T;T;T;T;T;T;D

Polyphen

0.95

P;.;.;.;.;.;.;P;.;.;P;.;.;.;.;.

Vest4

0.47

MutPred

0.53

Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);

MVP

0.33

MPC

0.94

ClinPred

0.73

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.23

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over