chr1-236686571-G-GCGCCCGCCGCCCGCCGCCCGC

Variant names:

• chr1-236686571-G-GCGCCCGCCGCCCGCCGCCCGC
• rs552471202
• NM_001103.4:c.-98_-78dupCGCCGCCCGCCGCCCGCCGCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001103.4(ACTN2):​c.-98_-78dupCGCCGCCCGCCGCCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 150,826 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 30)
• Consequence: ACTN2 NM_001103.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.-98_-78dupCGCCGCCCGCCGCCCGCCGCC		5_prime_UTR	Exon 1 of 21	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.-98_-78dupCGCCGCCCGCCGCCCGCCGCC		5_prime_UTR	Exon 1 of 21	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.78_98dupCGCCGCCCGCCGCCCGCCGCC		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.-98_-78dupCGCCGCCCGCCGCCCGCCGCC		5_prime_UTR	Exon 1 of 21	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.-98_-78dupCGCCGCCCGCCGCCCGCCGCC		5_prime_UTR	Exon 1 of 21	ENSP00000443495.1	P35609-2
	ACTN2	ENST00000879537.1		c.-98_-78dupCGCCGCCCGCCGCCCGCCGCC		5_prime_UTR	Exon 1 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150826 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 20

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150826 Hom.: 0 Cov.: 30 AF XY: 0.0000272 AC XY: 2 AN XY: 73654

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

African (AFR) AF: 0.00 AC: 0 AN: 41108

American (AMR) AF: 0.000199 AC: 3 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67656

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000945577), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73

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;