chr1-236686652-C-T

Position:

• chr1-236686652-C-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.-22C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,546,342 control chromosomes in the GnomAD database, including 940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (52 hom., cov: 31)
  • Exomes 𝑓: 0.032 (888 hom.)
• Consequence: ACTN2 NM_001103.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.85

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=-0.54).
• BP6: Variant 1-236686652-C-T is Benign according to our data. Variant chr1-236686652-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236686652-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.-22C>T		5_prime_UTR_variant	1/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.-22C>T		5_prime_UTR_variant	1/21
ACTN2	NR_184402.1	n.154C>T		non_coding_transcript_exon_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.-22C>T		5_prime_UTR_variant	1/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3500 AN: 151696 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.00699

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0647

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0360

GnomAD3 exomes AF: 0.0262 AC: 5422 AN: 206788 Hom.: 84 AF XY: 0.0273 AC XY: 3108 AN XY: 113942

Gnomad AFR exome AF: 0.00532

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0658

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0169

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0323 AC: 45039 AN: 1394538 Hom.: 888 Cov.: 31 AF XY: 0.0321 AC XY: 22308 AN XY: 693882

Gnomad4 AFR exome AF: 0.00634

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.0651

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0355

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0230 AC: 3499 AN: 151804 Hom.: 52 Cov.: 31 AF XY: 0.0221 AC XY: 1641 AN XY: 74226

Gnomad4 AFR AF: 0.00697

Gnomad4 AMR AF: 0.0250

Gnomad4 ASJ AF: 0.0647

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.0338

Gnomad4 OTH AF: 0.0351

Alfa AF: 0.0333 Hom.: 29

Bravo AF: 0.0233

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2013	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. -

Dilated cardiomyopathy 1AA Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	-0.54
CADD	Benign	17
DANN	Uncertain	0.98

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: rs138279482; hg19: chr1-236849952;