Variant rs536277584 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The ENST00000343373.10(DMPK):c.1693C>T(p.Gln565Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000136 in 1,474,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

DMPK
ENST00000343373.10 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07

Variant links:

Genes affected

DMPK (HGNC:2933): (DM1 protein kinase) The protein encoded by this gene is a serine-threonine kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. The 3' untranslated region of this gene contains 5-38 copies of a CTG trinucleotide repeat. Expansion of this unstable motif to 50-5,000 copies causes myotonic dystrophy type I, which increases in severity with increasing repeat element copy number. Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2016]

DMPK links:

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

DM1-AS links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in ENST00000343373.10 Downstream stopcodon found after 50 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMPK	NM_004409.5 linkuse as main transcript	c.1697C>T	p.Pro566Leu	missense_variant	14/15	ENST00000291270.9
DM1-AS	NR_147193.1 linkuse as main transcript	n.337-479G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMPK	ENST00000291270.9 linkuse as main transcript	c.1697C>T	p.Pro566Leu	missense_variant	14/15	5	NM_004409.5	A2	Q09013-9
DM1-AS	ENST00000590076.2 linkuse as main transcript	n.337-479G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD4 exome

AF:

7.56e-7

AC:

AN:

1322482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

647520

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000146

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myotonic dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.2

M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.28

N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.74

P;.;.

Vest4

0.46

MutPred

0.23

Gain of catalytic residue at P566 (P = 0.0647);.;.;

MVP

0.81

MPC

0.96

ClinPred

0.89

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over