rs527221

Positions:

• chr19-45772718-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1141 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11438 hom.)
• Consequence: DMPK NM_004409.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.11

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 -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 id is 128903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45772718-G-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DMPK	NM_004409.5	c.1267C>G	p.Leu423Val	missense_variant	10/15	ENST00000291270.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMPK	ENST00000291270.9	c.1267C>G	p.Leu423Val	missense_variant	10/15	5	NM_004409.5	A2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17223 AN: 152142 Hom.: 1144 Cov.: 33

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

GnomAD3 exomes AF: 0.138 AC: 22890 AN: 165710 Hom.: 1811 AF XY: 0.141 AC XY: 13051 AN XY: 92256

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 SAS exome AF: 0.222

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.: 30 AF XY: 0.127 AC XY: 85777 AN XY: 675440

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.113 AC: 17225 AN: 152260 Hom.: 1141 Cov.: 33 AF XY: 0.116 AC XY: 8643 AN XY: 74458

Gnomad4 AFR AF: 0.0651

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.130

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 06, 2013

- -

DMPK-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.80	D
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	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
MutationTaster	Benign	0.085	P;P;P;P;P;P
PrimateAI	Uncertain	0.51	T
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	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs527221; hg19: chr19-46275976; COSMIC: COSV52177670; COSMIC: COSV52177670;