Genetic Variant DYTN:p.Ser482Asn (chr2-206663091-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001093730.1(DYTN):c.1445G>A(p.Ser482Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DYTN
NM_001093730.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.954

Publications

4 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049214363).

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.1445G>A	p.Ser482Asn	missense	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.1445G>A	p.Ser482Asn	missense	Exon 11 of 12	ENSP00000396593.2	A2CJ06
	DYTN	ENST00000674258.1		n.1996G>A		non_coding_transcript_exon	Exon 14 of 15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

249018

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.34

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.0022

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.37

M_CAP

Benign

0.0049

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

PhyloP100

-0.95

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.50

REVEL

Benign

0.0080

Sift

Uncertain

0.021

Sift4G

Benign

0.43

Polyphen

0.012

Vest4

0.081

MutPred

0.15

Gain of helix (P = 0.0078)

MVP

0.014

MPC

0.026

ClinPred

0.029

GERP RS

-1.2

Varity_R

0.056

gMVP

0.093

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over