rs141629958

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004409.5(DMPK):c.882+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,613,900 control chromosomes in the GnomAD database, including 41 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 40 hom. )

Consequence

DMPK
NM_004409.5 splice_region, intron

Scores

Splicing: ADA: 0.00001120

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.28

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 19-45777659-G-A is Benign according to our data. Variant chr19-45777659-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45777659-G-A is described in Lovd as [Benign]. Variant chr19-45777659-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00503 (7346/1461538) while in subpopulation MID AF= 0.0186 (107/5768). AF 95% confidence interval is 0.0175. There are 40 homozygotes in gnomad4_exome. There are 3973 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 40 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMPK	NM_004409.5 link	c.882+8C>T		splice_region_variant, intron_variant	Intron 7 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.882+8C>T		splice_region_variant, intron_variant	Intron 7 of 14	5	NM_004409.5	ENSP00000291270.4		Q09013-9

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

582

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00811

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.000564

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00564

AC:

1416

AN:

251006

Hom.:

AF XY:

0.00645

AC XY:

876

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00654

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0183

Gnomad FIN exome

AF:

0.000925

Gnomad NFE exome

AF:

0.00438

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00503

AC:

7346

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

3973

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00684

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0182

Gnomad4 FIN exome

AF:

0.000941

Gnomad4 NFE exome

AF:

0.00433

Gnomad4 OTH exome

AF:

0.00540

GnomAD4 genome

AF:

0.00383

AC:

584

AN:

152362

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.000564

Gnomad4 NFE

AF:

0.00429

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00392

Hom.:

Bravo

AF:

0.00397

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

-0.89

CADD

Benign

0.12

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.0020

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

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