ENST00000651187.1:c.-91+9341C>T

Variant names:

• chr1-236686451-C-T
• rs951644250
• ENST00000651187.1:c.-91+9341C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000651187.1(ACTN2):​c.-91+9341C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 193,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: ACTN2 ENST00000651187.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BS2: High AC in GnomAd4 at 19 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000651187.1. 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.-223C>T		upstream_gene	N/A	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.-223C>T		upstream_gene	N/A	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.-48C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000651187.1		c.-91+9341C>T		intron	N/A	ENSP00000498348.1	A0A494C031
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.-223C>T		upstream_gene	N/A	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.-223C>T		upstream_gene	N/A	ENSP00000443495.1	P35609-2

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 19 AN: 148366 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000255

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000333 AC: 15 AN: 45000 Hom.: 0 Cov.: 3 AF XY: 0.000218 AC XY: 5 AN XY: 22928

African (AFR) AF: 0.00 AC: 0 AN: 938

American (AMR) AF: 0.00 AC: 0 AN: 364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 560

East Asian (EAS) AF: 0.00 AC: 0 AN: 894

South Asian (SAS) AF: 0.00 AC: 0 AN: 1582

European-Finnish (FIN) AF: 0.000853 AC: 1 AN: 1172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.000372 AC: 14 AN: 37604

Other (OTH) AF: 0.00 AC: 0 AN: 1768

GnomAD4 genome AF: 0.000128 AC: 19 AN: 148470 Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 12 AN XY: 72324

African (AFR) AF: 0.0000243 AC: 1 AN: 41080

American (AMR) AF: 0.00 AC: 0 AN: 14966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4996

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000255 AC: 17 AN: 66562

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.99
PhyloP100		1.9
PromoterAI		0.086	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs951644250; hg19: chr1-236849751;