rs2275998

Positions:

• chr11-66559110-T-A
• chr11-66559110-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001104.4(ACTN3):​c.1277-126T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: ACTN3 NM_001104.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.685

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]

ENSG00000250105 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.1277-126T>A		intron_variant		ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.1406-126T>A		intron_variant			NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.1277-126T>A		intron_variant		1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.1406-126T>A		intron_variant		2		ENSP00000422007.1
ENSG00000250105	ENST00000504911.1	n.336A>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

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.: 12

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74182

Gnomad4 AFR AF: 0.0000726

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.66

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: rs2275998; hg19: chr11-66326581;