1-236725990-G-T

Variant names:

• chr1-236725990-G-T
• NM_001103.4:c.506G>T

Variant summary

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

The NM_001103.4(ACTN2):​c.506G>T​(p.Arg169Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R169T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.506G>T	p.Arg169Ile	missense_variant	Exon 5 of 21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.506G>T	p.Arg169Ile	missense_variant	Exon 5 of 21		NP_001265272.1
ACTN2	NR_184402.1	n.681G>T		non_coding_transcript_exon_variant	Exon 5 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.506G>T	p.Arg169Ile	missense_variant	Exon 5 of 21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.052	T;D
Polyphen		0.70	.;P
Vest4		0.50
MutPred		0.41		Loss of solvent accessibility (P = 0.0159);Loss of solvent accessibility (P = 0.0159);
MVP		0.82
MPC		2.5
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-236889290;