dbSNP rs79969810: DYTN:p.Ser482Thr (chr2-206663091-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001093730.1(DYTN):c.1445G>C(p.Ser482Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,848 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S482N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0096 ( 27 hom., cov: 30)

Exomes 𝑓: 0.00097 ( 21 hom. )

Consequence

DYTN
NM_001093730.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.954

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045579374).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00955 (1454/152174) while in subpopulation AFR AF= 0.0319 (1325/41500). AF 95% confidence interval is 0.0305. There are 27 homozygotes in gnomad4. There are 684 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYTN	NM_001093730.1 link	c.1445G>C	p.Ser482Thr	missense_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.1445G>C	p.Ser482Thr	missense_variant	Exon 11 of 12	1	NM_001093730.1	ENSP00000396593.2		A2CJ06
DYTN	ENST00000674258.1 link	n.1996G>C		non_coding_transcript_exon_variant	Exon 14 of 15

Frequencies

GnomAD3 genomes

AF:

0.00942

AC:

1433

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00218

AC:

544

AN:

249018

Hom.:

AF XY:

0.00164

AC XY:

221

AN XY:

135092

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000969

AC:

1417

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000813

AC XY:

591

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0318

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.00955

AC:

1454

AN:

152174

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

684

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0319

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.000799

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0271

AC:

106

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00242

AC:

292

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.14

DANN

Benign

0.36

DEOGEN2

Benign

0.0011

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.22

REVEL

Benign

0.0040

Sift

Benign

0.58

Sift4G

Benign

0.96

Polyphen

0.0

Vest4

0.074

MVP

0.014

MPC

0.026

ClinPred

0.0042

GERP RS

-1.2

Varity_R

0.037

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over