1-236720121-C-T

Position:

• chr1-236720121-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001103.4(ACTN2):​c.378C>T​(p.Asn126Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,611,842 control chromosomes in the GnomAD database, including 776,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66858 hom., cov: 33)
  • Exomes 𝑓: 0.99 (709267 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.102

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-236720121-C-T is Benign according to our data. Variant chr1-236720121-C-T is described in ClinVar as [Benign]. Clinvar id is 43938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.378C>T	p.Asn126Asn	synonymous_variant	4/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.378C>T	p.Asn126Asn	synonymous_variant	4/21		NP_001265272.1
ACTN2	NR_184402.1	n.553C>T		non_coding_transcript_exon_variant	4/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.378C>T	p.Asn126Asn	synonymous_variant	4/21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142084 AN: 152138 Hom.: 66832 Cov.: 33

Gnomad AFR AF: 0.814

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.897

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.987

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.948

GnomAD3 exomes AF: 0.961 AC: 241683 AN: 251374 Hom.: 116634 AF XY: 0.968 AC XY: 131503 AN XY: 135854

Gnomad AFR exome AF: 0.817

Gnomad AMR exome AF: 0.871

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.980

Gnomad SAS exome AF: 0.971

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.995

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.985 AC: 1437881 AN: 1459586 Hom.: 709267 Cov.: 35 AF XY: 0.986 AC XY: 715849 AN XY: 726288

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.872

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.984

Gnomad4 SAS exome AF: 0.971

Gnomad4 FIN exome AF: 0.989

Gnomad4 NFE exome AF: 0.996

Gnomad4 OTH exome AF: 0.977

GnomAD4 genome AF: 0.934 AC: 142161 AN: 152256 Hom.: 66858 Cov.: 33 AF XY: 0.933 AC XY: 69421 AN XY: 74444

Gnomad4 AFR AF: 0.814

Gnomad4 AMR AF: 0.896

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.970

Gnomad4 FIN AF: 0.987

Gnomad4 NFE AF: 0.996

Gnomad4 OTH AF: 0.949

Alfa AF: 0.980 Hom.: 90171

Bravo AF: 0.921

Asia WGS AF: 0.963 AC: 3351 AN: 3478

EpiCase AF: 0.996

EpiControl AF: 0.995

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2011	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Myopathy, congenital, with structured cores and z-line abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.6
DANN	Benign	0.67

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: rs1341863; hg19: chr1-236883421;