X-101231690-C-T

Variant names:

• chrX-101231690-C-T
• rs756695526
• NM_001939.3:c.43C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_Strong PP5 BS2_Supporting

The NM_001939.3(DRP2):​c.43C>T​(p.Arg15*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,098,084 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: DRP2 NM_001939.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.31

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.985 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PP5: Variant X-101231690-C-T is Pathogenic according to our data. Variant chrX-101231690-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 807792.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.43C>T	p.Arg15*	stop_gained	Exon 3 of 24	ENST00000395209.8	NP_001930.2
DRP2	XM_047441894.1	c.43C>T	p.Arg15*	stop_gained	Exon 2 of 23		XP_047297850.1
DRP2	XM_017029333.2	c.43C>T	p.Arg15*	stop_gained	Exon 3 of 23		XP_016884822.1
DRP2	NM_001171184.2	c.-117-4170C>T		intron_variant	Intron 1 of 21		NP_001164655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRP2	ENST00000395209.8	c.43C>T	p.Arg15*	stop_gained	Exon 3 of 24	1	NM_001939.3	ENSP00000378635.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183150 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67642

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: 0.0000118 AC: 13 AN: 1098084 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 363448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.0000143

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2023	This sequence change creates a premature translational stop signal (p.Arg15*) in the DRP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DRP2 are known to be pathogenic (PMID: 22764250, 26227883). This variant is present in population databases (rs756695526, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with DRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 807792). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	DRP2: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.77
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs756695526; hg19: chrX-100486679;