1-236686682-G-C

Variant names:

• chr1-236686682-G-C
• rs1553295387
• NM_001103.4:c.9G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001103.4(ACTN2):​c.9G>C​(p.Gln3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• 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):

• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32016447).

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.9G>C	p.Gln3His	missense	Exon 1 of 21	NP_001094.1
	ACTN2	NM_001278343.2		c.9G>C	p.Gln3His	missense	Exon 1 of 21	NP_001265272.1
	ACTN2	NR_184402.1		n.184G>C		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.9G>C	p.Gln3His	missense	Exon 1 of 21	ENSP00000355537.4
	ACTN2	ENST00000542672.7	TSL:1	c.9G>C	p.Gln3His	missense	Exon 1 of 21	ENSP00000443495.1
	ACTN2	ENST00000682015.1		c.9G>C	p.Gln3His	missense	Exon 1 of 20	ENSP00000506961.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410498 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 701840

African (AFR) AF: 0.00 AC: 0 AN: 29004

American (AMR) AF: 0.00 AC: 0 AN: 39510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24262

East Asian (EAS) AF: 0.00 AC: 0 AN: 33858

South Asian (SAS) AF: 0.00 AC: 0 AN: 81820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1086288

Other (OTH) AF: 0.00 AC: 0 AN: 57576

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	D
Sift4G	Benign	0.093	T
Polyphen		0.83	P
Vest4		0.38
MutPred		0.13		Gain of catalytic residue at E5 (P = 0.1842)
MVP		0.81
MPC		1.2
ClinPred		0.48	T
GERP RS		3.7
PromoterAI		-0.063	Neutral
Varity_R		0.089
gMVP		0.84
Mutation Taster		=86/14	polymorphism

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: rs1553295387; hg19: chr1-236849982;