1-236686685-A-G

Position:

• chr1-236686685-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001103.4(ACTN2):​c.12A>G​(p.Ile4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,409,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0410

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1002861).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000638 (9/1409724) while in subpopulation MID AF= 0.00055 (3/5452). AF 95% confidence interval is 0.000149. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.12A>G	p.Ile4Met	missense_variant	1/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.12A>G	p.Ile4Met	missense_variant	1/21		NP_001265272.1
ACTN2	NR_184402.1	n.187A>G		non_coding_transcript_exon_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.12A>G	p.Ile4Met	missense_variant	1/21	1	NM_001103.4	ENSP00000355537	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000924 AC: 2 AN: 216506 Hom.: 0 AF XY: 0.00000843 AC XY: 1 AN XY: 118618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000746

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 9 AN: 1409724 Hom.: 0 Cov.: 31 AF XY: 0.00000713 AC XY: 5 AN XY: 701488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000489

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2021

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4 of the ACTN2 protein (p.Ile4Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1041227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.27	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.71	N;N
REVEL	Benign	0.25
Sift	Benign	0.69	T;T
Sift4G	Benign	0.91	T;T
Polyphen		0.0010	.;B
Vest4		0.17
MutPred		0.18		Loss of catalytic residue at I4 (P = 0.0226);Loss of catalytic residue at I4 (P = 0.0226);
MVP		0.58
MPC		0.87
ClinPred		0.035	T
GERP RS		-7.5
Varity_R		0.049
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs781720338; hg19: chr1-236849985;