1-236763145-T-C

Position:

• chr1-236763145-T-C

Variant summary

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

The ENST00000366578.6(ACTN2):​c.*526T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 160,716 control chromosomes in the GnomAD database, including 37,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34642 hom., cov: 33)
  • Exomes 𝑓: 0.73 (2388 hom.)
• Consequence: ACTN2 ENST00000366578.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.19

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=-0.81).
• BP6: Variant 1-236763145-T-C is Benign according to our data. Variant chr1-236763145-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 296518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.*526T>C		3_prime_UTR_variant	21/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.*526T>C		3_prime_UTR_variant	21/21		NP_001265272.1
ACTN2	NR_184402.1	n.3583T>C		non_coding_transcript_exon_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.*526T>C		3_prime_UTR_variant	21/21	1	NM_001103.4	ENSP00000355537	A1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101500 AN: 151958 Hom.: 34631 Cov.: 33

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.730 AC: 6309 AN: 8640 Hom.: 2388 Cov.: 0 AF XY: 0.716 AC XY: 3265 AN XY: 4560

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.749

Gnomad4 ASJ exome AF: 0.760

Gnomad4 EAS exome AF: 0.478

Gnomad4 SAS exome AF: 0.601

Gnomad4 FIN exome AF: 0.717

Gnomad4 NFE exome AF: 0.776

Gnomad4 OTH exome AF: 0.694

GnomAD4 genome AF: 0.668 AC: 101550 AN: 152076 Hom.: 34642 Cov.: 33 AF XY: 0.659 AC XY: 49007 AN XY: 74332

Gnomad4 AFR AF: 0.560

Gnomad4 AMR AF: 0.685

Gnomad4 ASJ AF: 0.768

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.640

Gnomad4 NFE AF: 0.752

Gnomad4 OTH AF: 0.651

Alfa AF: 0.732 Hom.: 53693

Bravo AF: 0.670

Asia WGS AF: 0.488 AC: 1698 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.3
DANN	Benign	0.75

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: rs1803032; hg19: chr1-236926445;