1-236686571-G-GCGCCCGC

Position:

• chr1-236686571-G-GCGCCCGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001103.4(ACTN2):​c.-84_-78dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,311,918 control chromosomes in the GnomAD database, including 224 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.033 (177 hom., cov: 30)
  • Exomes 𝑓: 0.0038 (47 hom.)
• Consequence: ACTN2 NM_001103.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.735

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 1-236686571-G-GCGCCCGC is Benign according to our data. Variant chr1-236686571-G-GCGCCCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296492.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.-84_-78dup		5_prime_UTR_variant	1/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.-84_-78dup		5_prime_UTR_variant	1/21		NP_001265272.1
ACTN2	NR_184402.1	n.92_98dup		non_coding_transcript_exon_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.-84_-78dup		5_prime_UTR_variant	1/21	1	NM_001103.4	ENSP00000355537	A1

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 4969 AN: 150772 Hom.: 174 Cov.: 30

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.0276

GnomAD4 exome AF: 0.00379 AC: 4405 AN: 1161050 Hom.: 47 Cov.: 20 AF XY: 0.00401 AC XY: 2272 AN XY: 566732

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.0454

Gnomad4 ASJ exome AF: 0.000271

Gnomad4 EAS exome AF: 0.00674

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.00617

GnomAD4 genome AF: 0.0331 AC: 4992 AN: 150868 Hom.: 177 Cov.: 30 AF XY: 0.0348 AC XY: 2563 AN XY: 73742

Gnomad4 AFR AF: 0.0697

Gnomad4 AMR AF: 0.0900

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.0326

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.0268

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs552471202; hg19: chr1-236849871;