NM_001103.4:c.771G>T

Variant names:

• chr1-236735708-G-T
• rs201545916
• NM_001103.4:c.771G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001103.4(ACTN2):​c.771G>T​(p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A257A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
• myopathy, congenital, with structured cores and z-line abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1AA

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• myopathy, distal, 6, adult-onset, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 1-236735708-G-T is Benign according to our data. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236735708-G-T is described in CliVar as Likely_benign. Clinvar id is 1620093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.33 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.771G>T	p.Ala257Ala	synonymous_variant	Exon 8 of 21	ENST00000366578.6	NP_001094.1
ACTN2	NR_184402.1	n.1032G>T		non_coding_transcript_exon_variant	Exon 9 of 23
ACTN2	NM_001278343.2	c.783+1190G>T		intron_variant	Intron 8 of 20		NP_001265272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.771G>T	p.Ala257Ala	synonymous_variant	Exon 8 of 21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		3.3
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs201545916; hg19: chr1-236899008; COSMIC: COSV100856632; COSMIC: COSV100856632;