dbSNP rs201920417: ACTN2:c.-3G>C (chr1-236686671-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001103.4(ACTN2):c.-3G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,403,550 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: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35

Publications

0 publications found

Variant links:

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):

intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
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)

ACTN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.-3G>C	5_prime_UTR_variant	Exon 1 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NR_184402.1 link	n.173G>C	non_coding_transcript_exon_variant	Exon 1 of 23
ACTN2	NM_001278343.2 link	c.-3G>C	5_prime_UTR_variant	Exon 1 of 21		NP_001265272.1	P35609-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.-3G>C		5_prime_UTR_variant	Exon 1 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1403550

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

698366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28692

American (AMR)

AF:

0.00

AC:

AN:

38482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24008

East Asian (EAS)

AF:

0.0000605

AC:

AN:

33070

South Asian (SAS)

AF:

0.00

AC:

AN:

81214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083028

Other (OTH)

AF:

0.00

AC:

AN:

57162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.3

PromoterAI

-0.24

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over