19-45771011-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004409.5(DMPK):c.1697C>G(p.Pro566Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000656 in 152,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P566L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

DMPK
NM_004409.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.07

Publications

1 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 links:

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

DM1-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2899086).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004409.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMPK	NM_004409.5	MANE Select	c.1697C>G	p.Pro566Arg	missense	Exon 14 of 15	NP_004400.4
DMPK	NM_001424163.1		c.1771C>G	p.Gln591Glu	missense	Exon 15 of 16	NP_001411092.1
DMPK	NM_001288764.2		c.1775C>G	p.Pro592Arg	missense	Exon 15 of 16	NP_001275693.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMPK	ENST00000291270.9	TSL:5 MANE Select	c.1697C>G	p.Pro566Arg	missense	Exon 14 of 15	ENSP00000291270.4
DMPK	ENST00000343373.10	TSL:1	c.1693C>G	p.Gln565Glu	missense	Exon 14 of 15	ENSP00000345997.4
DMPK	ENST00000447742.6	TSL:1	c.1682C>G	p.Pro561Arg	missense	Exon 14 of 15	ENSP00000413417.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

76048

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.0000126

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

PhyloP100

4.1

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.15

REVEL

Benign

0.28

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

0.59

Vest4

0.52

MutPred

0.23

Gain of MoRF binding (P = 0.0134)

MVP

0.69

MPC

0.99

ClinPred

0.90

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.22

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over