chr19-45770204-C-CCAG

Variant names:

• chr19-45770204-C-CCAG
• NM_004409.5:c.*281_*283dupCTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004409.5(DMPK):​c.*281_*283dupCTG 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
• 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]

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2812 AD gene.

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.*281_*283dupCTG		3_prime_UTR	Exon 15 of 15	NP_004400.4
	DMPK	NM_001424163.1		c.*274_*276dupCTG		3_prime_UTR	Exon 16 of 16	NP_001411092.1
	DMPK	NM_001288764.2		c.*281_*283dupCTG		3_prime_UTR	Exon 16 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.*281_*283dupCTG		3_prime_UTR	Exon 15 of 15	ENSP00000291270.4	Q09013-9
	DMPK	ENST00000343373.10	TSL:1	c.*274_*276dupCTG		3_prime_UTR	Exon 15 of 15	ENSP00000345997.4	Q09013-16
	DMPK	ENST00000447742.6	TSL:1	c.*281_*283dupCTG		3_prime_UTR	Exon 15 of 15	ENSP00000413417.1	Q09013-11

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

African (AFR) AF: 0.00641 AC: 92 AN: 14346

American (AMR) AF: 0.0118 AC: 364 AN: 30936

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 354 AN: 17506

East Asian (EAS) AF: 0.00725 AC: 221 AN: 30494

South Asian (SAS) AF: 0.0113 AC: 665 AN: 58958

European-Finnish (FIN) AF: 0.0431 AC: 1409 AN: 32694

Middle Eastern (MID) AF: 0.0205 AC: 50 AN: 2434

European-Non Finnish (NFE) AF: 0.0281 AC: 9750 AN: 347338

Other (OTH) AF: 0.0226 AC: 671 AN: 29712

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

African (AFR) AF: 0.00624 AC: 255 AN: 40870

American (AMR) AF: 0.0117 AC: 176 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 63 AN: 3446

East Asian (EAS) AF: 0.00519 AC: 26 AN: 5008

South Asian (SAS) AF: 0.0116 AC: 54 AN: 4656

European-Finnish (FIN) AF: 0.0483 AC: 495 AN: 10254

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0240 AC: 1618 AN: 67378

Other (OTH) AF: 0.0188 AC: 39 AN: 2074

Alfa AF: 0.0316 Hom.: 128

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Steinert myotonic dystrophy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=94/6	polymorphism

Splicing

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

Other links and lift over

hg19: chr19-46273462;