1-236731263-A-T

Variant names:

• chr1-236731263-A-T
• rs749019847
• NM_001103.4:c.646A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001103.4(ACTN2):​c.646A>T​(p.Met216Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M216V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.54
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.259522).

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.646A>T	p.Met216Leu	missense	Exon 7 of 21	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.646A>T	p.Met216Leu	missense	Exon 7 of 21	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.821A>T		non_coding_transcript_exon	Exon 7 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.646A>T	p.Met216Leu	missense	Exon 7 of 21	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.646A>T	p.Met216Leu	missense	Exon 7 of 21	ENSP00000443495.1	P35609-2
	ACTN2	ENST00000879537.1		c.646A>T	p.Met216Leu	missense	Exon 7 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111764

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.77	N
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.043	D
Polyphen		0.0080	B
Vest4		0.46
MutPred		0.64		Loss of methylation at K221 (P = 0.0692)
MVP		0.72
MPC		0.79
ClinPred		0.81	D
GERP RS		5.0
PromoterAI		-0.024	Neutral
Varity_R		0.62
gMVP		0.70
Mutation Taster		=72/28	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: rs749019847; hg19: chr1-236894563;