X-101231676-C-T

Position:

• chrX-101231676-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001939.3(DRP2):​c.29C>T​(p.Pro10Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,097,880 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: DRP2 NM_001939.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.62

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_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2035105).
• 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/exons	MANE	Protein	UniProt
DRP2	NM_001939.3	c.29C>T	p.Pro10Leu	missense_variant	3/24	ENST00000395209.8	NP_001930.2
DRP2	XM_047441894.1	c.29C>T	p.Pro10Leu	missense_variant	2/23		XP_047297850.1
DRP2	XM_017029333.2	c.29C>T	p.Pro10Leu	missense_variant	3/23		XP_016884822.1
DRP2	NM_001171184.2	c.-117-4184C>T		intron_variant			NP_001164655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRP2	ENST00000395209.8	c.29C>T	p.Pro10Leu	missense_variant	3/24	1	NM_001939.3	ENSP00000378635.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097880 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 363246

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: 0.0000493

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.29C>T (p.P10L) alteration is located in exon 3 (coding exon 1) of the DRP2 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the proline (P) at amino acid position 10 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 27, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 10 of the DRP2 protein (p.Pro10Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DRP2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DRP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0089	T;T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	.;.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.073
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.0010	B;B;B
Vest4		0.15
MutPred		0.31		Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);
MVP		0.75
MPC		0.41
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs909100703; hg19: chrX-100486665; COSMIC: COSV100871919;