DMPK p.Arg311*

Variant names:

• chr19-45779340-T-A
• NM_004409.5:c.356A>T
• DMPK p.Glu119Val

Your query was ambiguous. Multiple possible variants found:

• chr19-45779340-T-A
• chr19-45777542-G-A
• chr19-45770314-CG-TA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004409.5(DMPK):​c.356A>T​(p.Glu119Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DMPK NM_004409.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.94
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ENSG00000268434 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

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.356A>T	p.Glu119Val	missense	Exon 4 of 15	NP_004400.4
	DMPK	NM_001424163.1		c.434A>T	p.Glu145Val	missense	Exon 5 of 16	NP_001411092.1
	DMPK	NM_001288764.2		c.434A>T	p.Glu145Val	missense	Exon 5 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.356A>T	p.Glu119Val	missense	Exon 4 of 15	ENSP00000291270.4	Q09013-9
	DMPK	ENST00000343373.10	TSL:1	c.356A>T	p.Glu119Val	missense	Exon 4 of 15	ENSP00000345997.4	Q09013-16
	DMPK	ENST00000447742.6	TSL:1	c.356A>T	p.Glu119Val	missense	Exon 4 of 15	ENSP00000413417.1	Q09013-11

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.85
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr19-46282598;