rs141629958

Variant names:

• chr19-45777659-G-A
• rs141629958
• NM_004409.5:c.882+8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 445722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 3973 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 584 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMPK	NM_004409.5	c.882+8C>T		splice_region_variant, intron_variant	Intron 7 of 14	ENST00000291270.9	NP_004400.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMPK	ENST00000291270.9	c.882+8C>T		splice_region_variant, intron_variant	Intron 7 of 14	5	NM_004409.5	ENSP00000291270.4

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152244 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00564 AC: 1416 AN: 251006 AF XY: 0.00645

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 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.: 40 Cov.: 31 AF XY: 0.00546 AC XY: 3973 AN XY: 727066

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00684 AC: 306 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0182 AC: 1572 AN: 86258

European-Finnish (FIN) AF: 0.000941 AC: 50 AN: 53120

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5768

European-Non Finnish (NFE) AF: 0.00433 AC: 4819 AN: 1111986

Other (OTH) AF: 0.00540 AC: 326 AN: 60386

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74504

African (AFR) AF: 0.00130 AC: 54 AN: 41586

American (AMR) AF: 0.00810 AC: 124 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4834

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00429 AC: 292 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00392 Hom.: 1

Bravo AF: 0.00397

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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
PhyloP100		-1.3
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141629958; hg19: chr19-46280917; COSMIC: COSV99353892; COSMIC: COSV99353892;