1-236763145-T-C

Variant names:

• chr1-236763145-T-C
• rs1803032
• NM_001103.4:c.*526T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001103.4(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 NM_001103.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.19
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
• myopathy, congenital, with structured cores and z-line abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1AA

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• myopathy, distal, 6, adult-onset, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.*526T>C		3_prime_UTR	Exon 21 of 21	NP_001094.1
	ACTN2	NR_184402.1		n.3583T>C		non_coding_transcript_exon	Exon 23 of 23
	ACTN2	NM_001278343.2		c.*526T>C		3_prime_UTR	Exon 21 of 21	NP_001265272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.*526T>C		3_prime_UTR	Exon 21 of 21	ENSP00000355537.4
	ACTN2	ENST00000542672.7	TSL:1	c.*526T>C		3_prime_UTR	Exon 21 of 21	ENSP00000443495.1
	ACTN2	ENST00000461367.2	TSL:3	n.1507T>C		non_coding_transcript_exon	Exon 6 of 6

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

African (AFR) AF: 0.519 AC: 27 AN: 52

American (AMR) AF: 0.749 AC: 1132 AN: 1512

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 38 AN: 50

East Asian (EAS) AF: 0.478 AC: 176 AN: 368

South Asian (SAS) AF: 0.601 AC: 641 AN: 1066

European-Finnish (FIN) AF: 0.717 AC: 162 AN: 226

Middle Eastern (MID) AF: 0.611 AC: 11 AN: 18

European-Non Finnish (NFE) AF: 0.776 AC: 3900 AN: 5028

Other (OTH) AF: 0.694 AC: 222 AN: 320

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

African (AFR) AF: 0.560 AC: 23200 AN: 41460

American (AMR) AF: 0.685 AC: 10477 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2665 AN: 3470

East Asian (EAS) AF: 0.448 AC: 2312 AN: 5162

South Asian (SAS) AF: 0.548 AC: 2640 AN: 4818

European-Finnish (FIN) AF: 0.640 AC: 6761 AN: 10570

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51096 AN: 67988

Other (OTH) AF: 0.651 AC: 1378 AN: 2116

Alfa AF: 0.727 Hom.: 66994

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1803032; hg19: chr1-236926445;