chr19-45781076-T-G

Variant names:

• chr19-45781076-T-G
• rs672348
• NM_004409.5:c.160+1117A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004409.5(DMPK):​c.160+1117A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,000 control chromosomes in the GnomAD database, including 16,381 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (16381 hom., cov: 31)
• Consequence: DMPK NM_004409.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 14 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ENSG00000268434 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMPK	NM_004409.5	c.160+1117A>C		intron_variant	Intron 1 of 14	ENST00000291270.9	NP_004400.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMPK	ENST00000291270.9	c.160+1117A>C		intron_variant	Intron 1 of 14	5	NM_004409.5	ENSP00000291270.4
ENSG00000268434	ENST00000595946.1	c.178+1117A>C		intron_variant	Intron 2 of 3	2		ENSP00000469741.1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69383 AN: 151882 Hom.: 16364 Cov.: 31

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.469

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.457 AC: 69431 AN: 152000 Hom.: 16381 Cov.: 31 AF XY: 0.464 AC XY: 34477 AN XY: 74280

African (AFR) AF: 0.370 AC: 15332 AN: 41434

American (AMR) AF: 0.589 AC: 9012 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1355 AN: 3462

East Asian (EAS) AF: 0.651 AC: 3361 AN: 5162

South Asian (SAS) AF: 0.597 AC: 2875 AN: 4814

European-Finnish (FIN) AF: 0.456 AC: 4828 AN: 10586

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31251 AN: 67934

Other (OTH) AF: 0.472 AC: 997 AN: 2112

Alfa AF: 0.453 Hom.: 23677

Bravo AF: 0.463

Asia WGS AF: 0.605 AC: 2103 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs672348; hg19: chr19-46284334;