1-236686571-GCGCCCGCCGCCCGC-GCGCCCGCCGCCCGCCGCCCGC

Variant names:

• chr1-236686571-G-GCGCCCGC
• rs552471202
• NM_001103.4:c.-84_-78dupCGCCGCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001103.4(ACTN2):​c.-84_-78dupCGCCGCC 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
• Publications: 1 publications found

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):

• ACTN2-related cardiac and skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intrinsic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: Laboratory for Molecular Medicine
• 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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 296492.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0861 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.-84_-78dupCGCCGCC		5_prime_UTR	Exon 1 of 21	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.-84_-78dupCGCCGCC		5_prime_UTR	Exon 1 of 21	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.92_98dupCGCCGCC		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.-84_-78dupCGCCGCC		5_prime_UTR	Exon 1 of 21	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.-84_-78dupCGCCGCC		5_prime_UTR	Exon 1 of 21	ENSP00000443495.1	P35609-2
	ACTN2	ENST00000879537.1		c.-84_-78dupCGCCGCC		5_prime_UTR	Exon 1 of 22	ENSP00000549596.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0352 AC: 759 AN: 21592

American (AMR) AF: 0.0454 AC: 397 AN: 8748

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 4 AN: 14754

East Asian (EAS) AF: 0.00674 AC: 165 AN: 24468

South Asian (SAS) AF: 0.0124 AC: 568 AN: 45624

European-Finnish (FIN) AF: 0.00478 AC: 178 AN: 37232

Middle Eastern (MID) AF: 0.00285 AC: 9 AN: 3158

European-Non Finnish (NFE) AF: 0.00213 AC: 2039 AN: 959114

Other (OTH) AF: 0.00617 AC: 286 AN: 46360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0697 AC: 2869 AN: 41184

American (AMR) AF: 0.0900 AC: 1361 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3454

East Asian (EAS) AF: 0.0139 AC: 71 AN: 5108

South Asian (SAS) AF: 0.0326 AC: 156 AN: 4790

European-Finnish (FIN) AF: 0.0124 AC: 128 AN: 10286

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00516 AC: 349 AN: 67644

Other (OTH) AF: 0.0268 AC: 56 AN: 2086

Alfa AF: 0.00259 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs552471202; hg19: chr1-236849871;