1-236744712-G-C

Variant names:

• chr1-236744712-G-C
• rs764031568
• NM_001103.4:c.1342G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_001103.4(ACTN2):​c.1342G>C​(p.Glu448Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E448K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.98
• Publications: 8 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• BP6: Variant 1-236744712-G-C is Benign according to our data. Variant chr1-236744712-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1395077.

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.1342G>C	p.Glu448Gln	missense	Exon 12 of 21	NP_001094.1
	ACTN2	NM_001278343.2		c.1342G>C	p.Glu448Gln	missense	Exon 12 of 21	NP_001265272.1
	ACTN2	NR_184402.1		n.1714G>C		non_coding_transcript_exon	Exon 14 of 23

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.1342G>C	p.Glu448Gln	missense	Exon 12 of 21	ENSP00000355537.4
	ACTN2	ENST00000542672.7	TSL:1	c.1342G>C	p.Glu448Gln	missense	Exon 12 of 21	ENSP00000443495.1
	ACTN2	ENST00000682015.1		c.1249G>C	p.Glu417Gln	missense	Exon 11 of 20	ENSP00000506961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251182 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Uncertain:1

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.37
Sift	Benign	0.14	T
Sift4G	Benign	0.081	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.71		Loss of ubiquitination at K443 (P = 0.0464)
MVP		0.78
MPC		0.82
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.49
Mutation Taster		=199/101	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: rs764031568; hg19: chr1-236908012;