chrX-101231657-A-G

Position:

• chrX-101231657-A-G

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.10A>G​(p.Met4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,096,972 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000015 (0 hom. 4 hem.)
• Consequence: DRP2 NM_001939.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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=0.0718717).
• 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/exons	MANE	Protein	UniProt
DRP2	NM_001939.3	c.10A>G	p.Met4Val	missense_variant	3/24	ENST00000395209.8	NP_001930.2
DRP2	XM_047441894.1	c.10A>G	p.Met4Val	missense_variant	2/23		XP_047297850.1
DRP2	XM_017029333.2	c.10A>G	p.Met4Val	missense_variant	3/23		XP_016884822.1
DRP2	NM_001171184.2	c.-117-4203A>G		intron_variant			NP_001164655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRP2	ENST00000395209.8	c.10A>G	p.Met4Val	missense_variant	3/24	1	NM_001939.3	ENSP00000378635.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183316 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1096972 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 4 AN XY: 362366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 28, 2022

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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt DRP2 protein function. ClinVar contains an entry for this variant (Variation ID: 1427871). This variant has not been reported in the literature in individuals affected with DRP2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the DRP2 protein (p.Met4Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0096	T;T;T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	.;.;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.0070	B;B;B
Vest4		0.30
MutPred		0.30		Gain of catalytic residue at M4 (P = 0.0233);Gain of catalytic residue at M4 (P = 0.0233);Gain of catalytic residue at M4 (P = 0.0233);
MVP		0.24
MPC		0.41
ClinPred		0.21	T
GERP RS		4.6
Varity_R		0.33
gMVP		0.60

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: rs1369949523; hg19: chrX-100486646;