1-236686571-GCGCCCGC-G

Position:

• chr1-236686571-GCGCCCGC-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001103.4(ACTN2):​c.-84_-78del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,312,918 control chromosomes in the GnomAD database, including 63 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 30)
  • Exomes 𝑓: 0.0021 (38 hom.)
• Consequence: ACTN2 NM_001103.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.94

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 1-236686571-GCGCCCGC-G is Benign according to our data. Variant chr1-236686571-GCGCCCGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 296493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1679/150916) while in subpopulation AFR AF= 0.0361 (1486/41214). AF 95% confidence interval is 0.0345. There are 25 homozygotes in gnomad4. There are 804 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1679 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.-84_-78del		5_prime_UTR_variant	1/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.-84_-78del		5_prime_UTR_variant	1/21		NP_001265272.1
ACTN2	NR_184402.1	n.92_98del		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_-78del		5_prime_UTR_variant	1/21	1	NM_001103.4	ENSP00000355537	A1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1671 AN: 150818 Hom.: 25 Cov.: 30

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00298

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00546

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.000583

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00581

GnomAD4 exome AF: 0.00214 AC: 2483 AN: 1162002 Hom.: 38 AF XY: 0.00205 AC XY: 1162 AN XY: 567226

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.00613

Gnomad4 ASJ exome AF: 0.0000678

Gnomad4 EAS exome AF: 0.00261

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.0111 AC: 1679 AN: 150916 Hom.: 25 Cov.: 30 AF XY: 0.0109 AC XY: 804 AN XY: 73762

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.00298

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00548

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.000583

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.00575

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;