Variant chr1-236686695-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001103.4(ACTN2):c.22G>T(p.Val8Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000707 in 1,414,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

Variant links:

Genes affected

ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACTN2 links:

ACTN2 (HGNC:):

ACTN2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18866915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4 linkuse as main transcript	c.22G>T	p.Val8Leu	missense_variant	1/21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 linkuse as main transcript	c.22G>T	p.Val8Leu	missense_variant	1/21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 linkuse as main transcript	n.197G>T		non_coding_transcript_exon_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.22G>T	p.Val8Leu	missense_variant	1/21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000457

AC:

AN:

218624

Hom.:

AF XY:

0.00

AC XY:

AN XY:

119668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000336

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000250

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:

0.00

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

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The p.V8L variant (also known as c.22G>T), located in coding exon 1 of the ACTN2 gene, results from a G to T substitution at nucleotide position 22. The valine at codon 8 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

L;L

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.20

Sift

Benign

0.58

T;T

Sift4G

Benign

0.84

T;T

Polyphen

0.0020

.;B

Vest4

0.081

MutPred

0.18

Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);

MVP

0.64

MPC

0.84

ClinPred

0.19

GERP RS

2.8

Varity_R

0.076

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over