rs540874

chr11-66562261-A-Cchr11-66562261-A-G

Variant summary

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

The NM_001104.4(ACTN3):c.2327A>C(p.Gln776Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Q776R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67

Genes affected

ACTN3 (HGNC:165): (actinin alpha 3) This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containing thin filaments. An allelic polymorphism in this gene results in both coding and non-coding variants; the reference genome represents the coding allele. The non-functional allele of this gene is associated with elite athlete status. [provided by RefSeq, Feb 2014]

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=0.25630307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN3	NM_001104.4	c.2327A>C	p.Gln776Pro	missense_variant	19/21	ENST00000513398.2
ACTN3	NM_001258371.3	c.2456A>C	p.Gln819Pro	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN3	ENST00000513398.2	c.2327A>C	p.Gln776Pro	missense_variant	19/21	1	NM_001104.4	P1
ACTN3	ENST00000502692.5	c.2456A>C	p.Gln819Pro	missense_variant	19/21	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.26	T;T
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.039	D;D
Polyphen		0.0050	.;B
Vest4		0.16
MVP		0.42
GERP RS		5.7
Varity_R		0.16
gMVP		0.83

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: rs540874; hg19: chr11-66329732;