19-45770204-C-CCAG

Position:

• chr19-45770204-C-CCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004409.5(DMPK):​c.*283_*284insCTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 0)
  • Exomes 𝑓: 0.024 (575 hom.)
• Consequence: DMPK NM_004409.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

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]

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

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 19-45770204-C-CCAG is Benign according to our data. Variant chr19-45770204-C-CCAG is described in ClinVar as [Benign]. Clinvar id is 810805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0188 (2812/149938) while in subpopulation NFE AF= 0.024 (1618/67378). AF 95% confidence interval is 0.023. There are 49 homozygotes in gnomad4. There are 1412 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMPK	NM_004409.5	c.*283_*284insCTG		3_prime_UTR_variant	15/15	ENST00000291270.9
DM1-AS	NR_147193.1	n.337-1226_337-1224dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMPK	ENST00000291270.9	c.*283_*284insCTG		3_prime_UTR_variant	15/15	5	NM_004409.5	A2
DM1-AS	ENST00000590076.2	n.337-1226_337-1224dup		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2812 AN: 149822 Hom.: 50 Cov.: 0

Gnomad AFR AF: 0.00626

Gnomad AMI AF: 0.0948

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0183

Gnomad EAS AF: 0.00518

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0185

GnomAD4 exome AF: 0.0241 AC: 13576 AN: 564418 Hom.: 575 Cov.: 0 AF XY: 0.0234 AC XY: 7013 AN XY: 300230

Gnomad4 AFR exome AF: 0.00641

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.00725

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0431

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0226

GnomAD4 genome AF: 0.0188 AC: 2812 AN: 149938 Hom.: 49 Cov.: 0 AF XY: 0.0193 AC XY: 1412 AN XY: 73104

Gnomad4 AFR AF: 0.00624

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0183

Gnomad4 EAS AF: 0.00519

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Steinert myotonic dystrophy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Neuromuscular Research, Maastricht University Medical Centre

Nov 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-46273462;