rs1341864

Variant names:

• chr1-236719003-T-C
• rs1341864
• NM_001103.4:c.351T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-236719003-T-C
• chr1-236719003-T-A
• chr1-236719003-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001103.4(ACTN2):​c.351T>C​(p.Ile117Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,614,080 control chromosomes in the GnomAD database, including 805,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75116 hom., cov: 31)
  • Exomes 𝑓: 1.0 (729960 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0370
• Publications: 20 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):

• ACTN2-related cardiac and skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intrinsic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: Laboratory for Molecular Medicine
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-236719003-T-C is Benign according to our data. Variant chr1-236719003-T-C is described in ClinVar as Benign. ClinVar VariationId is 43937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.351T>C	p.Ile117Ile	synonymous	Exon 3 of 21	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.351T>C	p.Ile117Ile	synonymous	Exon 3 of 21	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.526T>C		non_coding_transcript_exon	Exon 3 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.351T>C	p.Ile117Ile	synonymous	Exon 3 of 21	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.351T>C	p.Ile117Ile	synonymous	Exon 3 of 21	ENSP00000443495.1	P35609-2
	ACTN2	ENST00000879537.1		c.351T>C	p.Ile117Ile	synonymous	Exon 3 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151124 AN: 152144 Hom.: 75062 Cov.: 31

Gnomad AFR AF: 0.978

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.998 AC: 251040 AN: 251446 AF XY: 0.999

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1460861 AN: 1461818 Hom.: 729960 Cov.: 61 AF XY: 0.999 AC XY: 726828 AN XY: 727218

African (AFR) AF: 0.978 AC: 32727 AN: 33478

American (AMR) AF: 0.999 AC: 44662 AN: 44720

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26132 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39697 AN: 39698

South Asian (SAS) AF: 1.00 AC: 86248 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53416 AN: 53416

Middle Eastern (MID) AF: 0.999 AC: 5740 AN: 5746

European-Non Finnish (NFE) AF: 1.00 AC: 1111938 AN: 1111984

Other (OTH) AF: 0.999 AC: 60301 AN: 60388

GnomAD4 genome AF: 0.993 AC: 151237 AN: 152262 Hom.: 75116 Cov.: 31 AF XY: 0.993 AC XY: 73941 AN XY: 74436

African (AFR) AF: 0.978 AC: 40627 AN: 41556

American (AMR) AF: 0.996 AC: 15207 AN: 15274

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4820 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10612 AN: 10612

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68025 AN: 68034

Other (OTH) AF: 0.991 AC: 2096 AN: 2116

Alfa AF: 0.998 Hom.: 44729

Bravo AF: 0.992

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myopathy, congenital, with structured cores and z-line abnormalities (1)
-	-	1	not provided (1)
-	-	1	Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.7
DANN	Benign	0.74
PhyloP100		0.037
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1341864; hg19: chr1-236882303; COSMIC: COSV108199734;