rs527221

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004409.5(DMPK):c.1267C>G(p.Leu423Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,515,054 control chromosomes in the GnomAD database, including 12,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1141 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11438 hom. )

Consequence

DMPK
NM_004409.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.11

Publications

41 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015607774).

BP6

Variant 19-45772718-G-C is Benign according to our data. Variant chr19-45772718-G-C is described in ClinVar as Benign. ClinVar VariationId is 128903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMPK	NM_004409.5 link	c.1267C>G	p.Leu423Val	missense_variant	Exon 10 of 15	ENST00000291270.9	NP_004400.4	Q09013-9E5KR06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMPK	ENST00000291270.9 link	c.1267C>G	p.Leu423Val	missense_variant	Exon 10 of 15	5	NM_004409.5	ENSP00000291270.4		Q09013-9

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17223

AN:

152142

Hom.:

1144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0651

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.135

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.138

AC:

22890

AN:

165710

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.0654

Gnomad AMR exome

AF:

0.221

Gnomad ASJ exome

AF:

0.123

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.124

AC:

169106

AN:

1362794

Hom.:

11438

Cov.:

AF XY:

0.127

AC XY:

85777

AN XY:

675440

show subpopulations

African (AFR)

AF:

0.0650

AC:

1737

AN:

26716

American (AMR)

AF:

0.195

AC:

4329

AN:

22204

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

2920

AN:

22906

East Asian (EAS)

AF:

0.184

AC:

5908

AN:

32038

South Asian (SAS)

AF:

0.227

AC:

15686

AN:

69246

European-Finnish (FIN)

AF:

0.141

AC:

7391

AN:

52434

Middle Eastern (MID)

AF:

0.146

AC:

805

AN:

5500

European-Non Finnish (NFE)

AF:

0.114

AC:

123078

AN:

1075574

Other (OTH)

AF:

0.129

AC:

7252

AN:

56176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

6456

12912

19367

25823

32279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4668

9336

14004

18672

23340

<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

AF:

0.113

AC:

17225

AN:

152260

Hom.:

1141

Cov.:

AF XY:

0.116

AC XY:

8643

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0651

AC:

2704

AN:

41564

American (AMR)

AF:

0.140

AC:

2138

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

459

AN:

3470

East Asian (EAS)

AF:

0.168

AC:

872

AN:

5178

South Asian (SAS)

AF:

0.234

AC:

1128

AN:

4824

European-Finnish (FIN)

AF:

0.135

AC:

1426

AN:

10590

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8112

AN:

68012

Other (OTH)

AF:

0.130

AC:

274

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

797

1594

2392

3189

3986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.117

Hom.:

356

Bravo

AF:

0.112

TwinsUK

AF:

0.106

AC:

394

ALSPAC

AF:

0.117

AC:

451

ESP6500AA

AF:

0.0672

AC:

296

ESP6500EA

AF:

0.113

AC:

971

ExAC

AF:

0.143

AC:

17387

Asia WGS

AF:

0.186

AC:

649

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 06, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DMPK-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.;.;.;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.83

T;T;T;T;.;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;.;.;.;.;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.26

N;.;N;N;N;.;N

REVEL

Benign

0.16

Sift

Benign

0.37

T;.;T;T;T;.;T

Sift4G

Benign

0.24

T;T;T;T;T;T;T

Polyphen

1.0

D;.;.;.;.;.;B

Vest4

0.17

MPC

0.51

ClinPred

0.022

GERP RS

3.9

PromoterAI

0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.084

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over