rs534558800

Variant names:

• chr2-206663253-T-TCC
• rs534558800
• NM_001093730.1:c.1281_1282dupGG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001093730.1(DYTN):​c.1281_1282dupGG​(p.Glu428GlyfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,976 control chromosomes in the GnomAD database, including 35 homozygotes. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (34 hom.)
• Consequence: DYTN NM_001093730.1 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.391
• Publications: 2 publications found

Genes affected

DYTN (HGNC:23279): (dystrotelin) This gene belongs to the dystrophin superfamily, which is characterized by the presence of four EF-hand motifs and a ZZ-domain. It is a likely ortholog of the Drosophila 'discontinuous actin hexagon' gene. It is noteworthy that the coding region of this gene lacks two coding exons that are found in the mouse ortholog. Human transcripts including these two exons are subject to nonsense-mediated transcript decay (NMD). On the other hand, transcripts skipping the two coding exons are expressed at very low levels. While this gene maintains an intact CDS, it may be an evolving pseudogene. However, after a discussion about this gene within the RefSeq group, as well as in the consensus coding sequence (CCDS) collaboration, it was decided to keep it as a protein-coding gene in the RefSeq, Ensembl-GENCODE and the CCDS sets. [provided by RefSeq, Jul 2019]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00348 (5084/1461704) while in subpopulation SAS AF = 0.018 (1555/86258). AF 95% confidence interval is 0.0173. There are 34 homozygotes in GnomAdExome4. There are 2895 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093730.1. 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
	DYTN	NM_001093730.1	MANE Select	c.1281_1282dupGG	p.Glu428GlyfsTer61	frameshift	Exon 11 of 12	NP_001087199.1	A2CJ06

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYTN	ENST00000452335.2	TSL:1 MANE Select	c.1281_1282dupGG	p.Glu428GlyfsTer61	frameshift	Exon 11 of 12	ENSP00000396593.2	A2CJ06
	DYTN	ENST00000674258.1		n.1832_1833dupGG		non_coding_transcript_exon	Exon 14 of 15

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00403 AC: 1004 AN: 249232 AF XY: 0.00488

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00348 AC: 5084 AN: 1461704 Hom.: 34 Cov.: 32 AF XY: 0.00398 AC XY: 2895 AN XY: 727134

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 219 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0180 AC: 1555 AN: 86258

European-Finnish (FIN) AF: 0.00221 AC: 118 AN: 53402

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00263 AC: 2920 AN: 1111868

Other (OTH) AF: 0.00316 AC: 191 AN: 60374

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74462

African (AFR) AF: 0.000578 AC: 24 AN: 41550

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4820

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00367 Hom.: 0

Bravo AF: 0.00174

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39
Mutation Taster		=76/124	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs534558800; hg19: chr2-207527977; COSMIC: COSV71752193;