rs141629958

chr19-45777659-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:3
• Conservation: PhyloP100: -1.28

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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 GnomAdExome at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMPK	NM_004409.5	c.882+8C>T		splice_region_variant, intron_variant		ENST00000291270.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMPK	ENST00000291270.9	c.882+8C>T		splice_region_variant, intron_variant		5	NM_004409.5	A2

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

GnomAD3 exomes AF: 0.00564 AC: 1416 AN: 251006 Hom.: 8 AF XY: 0.00645 AC XY: 876 AN XY: 135750

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

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.: 1 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74504

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.: 1

Bravo AF: 0.00397

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

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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

Other links and lift over

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