NM_004409.5:c.581+6T>C

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.581+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,612,250 control chromosomes in the GnomAD database, including 199,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22710 hom., cov: 33)

Exomes 𝑓: 0.49 ( 176749 hom. )

Consequence

DMPK
NM_004409.5 splice_region, intron

Scores

Splicing: ADA: 0.0008222

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.22

Publications

19 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 Gene-Disease associations (from GenCC):

myotonic dystrophy type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

DMPK 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 (BayesDel_noAF=-0.85).

BP6

Variant 19-45778487-A-G is Benign according to our data. Variant chr19-45778487-A-G is described in ClinVar as Benign. ClinVar VariationId is 128902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMPK	NM_004409.5 link	c.581+6T>C		splice_region_variant, intron_variant	Intron 5 of 14	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.581+6T>C		splice_region_variant, intron_variant	Intron 5 of 14	5	NM_004409.5	ENSP00000291270.4		Q09013-9

Frequencies

GnomAD3 genomes

AF:

0.538

AC:

81710

AN:

151920

Hom.:

22669

Cov.:

show subpopulations

Gnomad AFR

AF:

0.649

Gnomad AMI

AF:

0.290

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.393

Gnomad EAS

AF:

0.651

Gnomad SAS

AF:

0.602

Gnomad FIN

AF:

0.458

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.462

Gnomad OTH

AF:

0.534

GnomAD2 exomes

AF:

0.534

AC:

133293

AN:

249404

AF XY:

0.527

show subpopulations

Gnomad AFR exome

AF:

0.652

Gnomad AMR exome

AF:

0.696

Gnomad ASJ exome

AF:

0.382

Gnomad EAS exome

AF:

0.641

Gnomad FIN exome

AF:

0.466

Gnomad NFE exome

AF:

0.462

Gnomad OTH exome

AF:

0.505

GnomAD4 exome

AF:

0.487

AC:

710486

AN:

1460212

Hom.:

176749

Cov.:

AF XY:

0.488

AC XY:

354327

AN XY:

726292

show subpopulations

African (AFR)

AF:

0.657

AC:

22001

AN:

33464

American (AMR)

AF:

0.685

AC:

30619

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

10145

AN:

26112

East Asian (EAS)

AF:

0.671

AC:

26617

AN:

39660

South Asian (SAS)

AF:

0.593

AC:

51181

AN:

86240

European-Finnish (FIN)

AF:

0.468

AC:

24728

AN:

52800

Middle Eastern (MID)

AF:

0.486

AC:

2781

AN:

5724

European-Non Finnish (NFE)

AF:

0.461

AC:

512695

AN:

1111206

Other (OTH)

AF:

0.493

AC:

29719

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

18318

36637

54955

73274

91592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15582

31164

46746

62328

77910

<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:

0.538

AC:

81810

AN:

152038

Hom.:

22710

Cov.:

AF XY:

0.542

AC XY:

40312

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.650

AC:

26953

AN:

41486

American (AMR)

AF:

0.620

AC:

9483

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.393

AC:

1362

AN:

3464

East Asian (EAS)

AF:

0.652

AC:

3365

AN:

5164

South Asian (SAS)

AF:

0.601

AC:

2898

AN:

4820

European-Finnish (FIN)

AF:

0.458

AC:

4832

AN:

10560

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.462

AC:

31363

AN:

67932

Other (OTH)

AF:

0.536

AC:

1130

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1918

3836

5755

7673

9591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.499

Hom.:

8642

Bravo

AF:

0.555

Asia WGS

AF:

0.624

AC:

2173

AN:

3478

EpiCase

AF:

0.457

EpiControl

AF:

0.454

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Steinert myotonic dystrophy syndrome

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.40

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00082

dbscSNV1_RF

Benign

0.096

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over