rs2288602

chr1-236739565-A-Cchr1-236739565-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001103.4(ACTN2):c.1107+33A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,607,840 control chromosomes in the GnomAD database, including 326,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (23142 hom., cov: 33)
  • Exomes 𝑓: 0.64 (303017 hom.)
• Consequence: ACTN2 NM_001103.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.494

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-236739565-A-C is Benign according to our data. Variant chr1-236739565-A-C is described in ClinVar as [Benign]. Clinvar id is 671062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1107+33A>C		intron_variant		ENST00000366578.6
ACTN2	NM_001278343.2	c.1107+33A>C		intron_variant
ACTN2	NR_184402.1	n.1479+33A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1107+33A>C		intron_variant		1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77757 AN: 152034 Hom.: 23143 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.524

GnomAD3 exomes AF: 0.580 AC: 137831 AN: 237546 Hom.: 41861 AF XY: 0.591 AC XY: 76011 AN XY: 128588

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.629

Gnomad EAS exome AF: 0.507

Gnomad SAS exome AF: 0.544

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.666

Gnomad OTH exome AF: 0.606

GnomAD4 exome AF: 0.639 AC: 929464 AN: 1455690 Hom.: 303017 Cov.: 42 AF XY: 0.638 AC XY: 461454 AN XY: 723692

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.475

Gnomad4 ASJ exome AF: 0.624

Gnomad4 EAS exome AF: 0.528

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.691

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.603

GnomAD4 genome AF: 0.511 AC: 77767 AN: 152150 Hom.: 23142 Cov.: 33 AF XY: 0.513 AC XY: 38140 AN XY: 74374

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.695

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.526

Alfa AF: 0.599 Hom.: 5394

Bravo AF: 0.479

Asia WGS AF: 0.473 AC: 1650 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.7
Dann	Benign	0.66

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: rs2288602; hg19: chr1-236902865; COSMIC: COSV63973384;