rs747348407

Variant names:

• chr19-45778159-C-T
• rs747348407
• NM_004409.5:c.643G>A
• DMPK p.Gly215Ser

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_Strong BS2_Supporting

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• BS2: High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMPK	NM_004409.5	MANE Select	c.643G>A	p.Gly215Ser	missense	Exon 6 of 15	NP_004400.4
	DMPK	NM_001424163.1		c.721G>A	p.Gly241Ser	missense	Exon 7 of 16	NP_001411092.1
	DMPK	NM_001288764.2		c.721G>A	p.Gly241Ser	missense	Exon 7 of 16	NP_001275693.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMPK	ENST00000291270.9	TSL:5 MANE Select	c.643G>A	p.Gly215Ser	missense	Exon 6 of 15	ENSP00000291270.4	Q09013-9
	DMPK	ENST00000343373.10	TSL:1	c.643G>A	p.Gly215Ser	missense	Exon 6 of 15	ENSP00000345997.4	Q09013-16
	DMPK	ENST00000447742.6	TSL:1	c.643G>A	p.Gly215Ser	missense	Exon 6 of 15	ENSP00000413417.1	Q09013-11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248302 AF XY: 0.0000223

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111788

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Myotonic dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.77
Mutation Taster		=70/30	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs747348407;

hg19: chr19-46281417;

COSMIC: COSV104539978;

COSMIC: COSV104539978;