rs1057519071

Variant names:

• chrX-101242967-C-T
• rs1057519071
• NM_001939.3:c.1039C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1 BS2_Supporting

The NM_001939.3(DRP2):​c.1039C>T​(p.Gln347*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000455 in 1,097,731 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: DRP2 NM_001939.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.17

Genes affected

DRP2 (HGNC:3032): (dystrophin related protein 2) Members of the dystrophin family of proteins perform a critical role in the maintenance of membrane-associated complexes at points of intercellular contact in vertebrate cells. The protein encoded by this gene is predicted to resemble certain short C-terminal isoforms of dystrophin and dystrophin-related protein 1 (DRP1 or utrophin). DRP2 is expressed principally in the brain and spinal cord. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Hemizygotes in GnomAdExome4 at 2 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRP2	NM_001939.3	c.1039C>T	p.Gln347*	stop_gained	Exon 9 of 24	ENST00000395209.8	NP_001930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRP2	ENST00000395209.8	c.1039C>T	p.Gln347*	stop_gained	Exon 9 of 24	1	NM_001939.3	ENSP00000378635.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183190 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097731 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 2 AN XY: 363097

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 17, 2015

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease X-linked dominant 1 Uncertain:1

May 05, 2025

Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was detected in a male patient with adult-onset axonal sensorimotor neuropathy confirmed by nerve conduction study. This nucleotide change leads to a premature termination codon in exon 9 out of a total of 24 exons. The transcript is predicted to undergo nonsense mediated decay. This variant is found at a very low frequency in control population database (0.0004%, gnomAD v4.1.0). The same variant was described in two hemizygous case reports in patients with Charcot-Marie-Tooth disease. Other loss of function variants in DRP2 causing Charcot-Marie-Tooth disease have been described. While the variant level evidence suggests this variant to be likely pathogenic, the gene disease association remains to be established and therefore this variant is currently classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.92
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 15

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519071; hg19: chrX-100497956;