Genetic Variant DYTN:p.Glu428GlyfsTer61 (chr2-206663253-T-TCC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

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).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 34 hom. )

Consequence

DYTN
NM_001093730.1 frameshift

Scores

Not classified

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.391

Variant links:

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]

DYTN links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 2895 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYTN	NM_001093730.1 link	c.1281_1282dupGG	p.Glu428GlyfsTer61	frameshift_variant	Exon 11 of 12	ENST00000452335.2	NP_001087199.1	A2CJ06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYTN	ENST00000452335.2 link	c.1281_1282dupGG	p.Glu428GlyfsTer61	frameshift_variant	Exon 11 of 12	1	NM_001093730.1	ENSP00000396593.2		A2CJ06
DYTN	ENST00000674258.1 link	n.1832_1833dupGG		non_coding_transcript_exon_variant	Exon 14 of 15

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

360

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00403

AC:

1004

AN:

249232

Hom.:

AF XY:

0.00488

AC XY:

660

AN XY:

135208

show subpopulations

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 SAS exome

AF:

0.0180

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.:

Cov.:

AF XY:

0.00398

AC XY:

2895

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00838

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0180

Gnomad4 FIN exome

AF:

0.00221

Gnomad4 NFE exome

AF:

0.00263

Gnomad4 OTH exome

AF:

0.00316

GnomAD4 genome

AF:

0.00237

AC:

361

AN:

152272

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00297

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00367

Hom.:

Bravo

AF:

0.00174

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00190

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over