chr19-45778159-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_004409.5(DMPK):​c.643G>A​(p.Gly215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

DMPK
NM_004409.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DMPKNM_004409.5 linkc.643G>A p.Gly215Ser missense_variant 6/15 ENST00000291270.9 NP_004400.4 Q09013-9E5KR06

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DMPKENST00000291270.9 linkc.643G>A p.Gly215Ser missense_variant 6/155 NM_004409.5 ENSP00000291270.4 Q09013-9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248302
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134698
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000656
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461180
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726848
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myotonic dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonOct 01, 2016Found in patient having exome sequencing for an unrelated indication. No known history of myotonic dystrophy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T;.;.;.;.;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D;.;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Uncertain
2.9
M;.;.;M;M;M;M
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.9
D;.;D;D;D;.;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;.;D;D;D;.;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.;D
Vest4
0.89
MutPred
0.96
Loss of catalytic residue at D213 (P = 0.2011);.;.;Loss of catalytic residue at D213 (P = 0.2011);Loss of catalytic residue at D213 (P = 0.2011);Loss of catalytic residue at D213 (P = 0.2011);Loss of catalytic residue at D213 (P = 0.2011);
MVP
0.91
MPC
1.1
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.89
gMVP
0.77

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747348407; hg19: chr19-46281417; COSMIC: COSV104539978; COSMIC: COSV104539978; API