NM_001103.4:c.-22C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.-22C>T	5_prime_UTR_variant	Exon 1 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.-22C>T	5_prime_UTR_variant	Exon 1 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.154C>T	non_coding_transcript_exon_variant	Exon 1 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578 link	c.-22C>T		5_prime_UTR_variant	Exon 1 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.0231

AC:

3500

AN:

151696

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0273

AC XY:

3108

AN XY:

113942

show subpopulations

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.:

AF XY:

0.0321

AC XY:

22308

AN XY:

693882

show subpopulations

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.:

Cov.:

AF XY:

0.0221

AC XY:

1641

AN XY:

74226

show subpopulations

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.:

Bravo

AF:

0.0233

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 16, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1AA

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

-0.54

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over