rs397516573

Positions:

• chr1-236759728-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001103.4(ACTN2):​c.2306A>C​(p.Lys769Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,216 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.16

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26223892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.2306A>C	p.Lys769Thr	missense_variant	19/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.2306A>C	p.Lys769Thr	missense_variant	19/21
ACTN2	NR_184402.1	n.2678A>C		non_coding_transcript_exon_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.2306A>C	p.Lys769Thr	missense_variant	19/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 19, 2012

The Lys769Thr variant in ACTN2 has not been reported in the literature nor previ ously identified by our laboratory. It was detected by our laboratory in 1 infan t with DCM (this individual). This individual was of African American ancestry and the variant was absent from >4,000 African American chromosomes screened by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/). This low frequency supports a role in disease. However, the affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other co mputational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, a nd SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of th is variant. -

Dilated cardiomyopathy 1AA Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KardioGenetik, Herz- und Diabeteszentrum NRW

Nov 16, 2023

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2020

The c.2306A>C (p.K769T) alteration is located in exon 19 (coding exon 19) of the ACTN2 gene. This alteration results from a A to C substitution at nucleotide position 2306, causing the lysine (K) at amino acid position 769 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	2.9	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	.;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	.;D;D
Sift4G	Uncertain	0.013	D;T;T
Polyphen		0.035	.;.;B
Vest4		0.32
MutPred		0.39		.;Loss of ubiquitination at K769 (P = 0.0074);Loss of ubiquitination at K769 (P = 0.0074);
MVP		0.85
MPC		0.30
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.26
gMVP		0.82

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: rs397516573; hg19: chr1-236923028;