X-101235864-G-A

Variant names:

• chrX-101235864-G-A
• rs1254070988
• NM_001939.3:c.122G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001939.3(DRP2):​c.122G>A​(p.Arg41Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000915 in 1,093,401 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DRP2 NM_001939.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087222695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRP2	NM_001939.3	c.122G>A	p.Arg41Lys	missense_variant	Exon 4 of 24	ENST00000395209.8	NP_001930.2
DRP2	XM_047441894.1	c.122G>A	p.Arg41Lys	missense_variant	Exon 3 of 23		XP_047297850.1
DRP2	XM_017029333.2	c.122G>A	p.Arg41Lys	missense_variant	Exon 4 of 23		XP_016884822.1
DRP2	NM_001171184.2	c.-113G>A		5_prime_UTR_variant	Exon 2 of 22		NP_001164655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRP2	ENST00000395209.8	c.122G>A	p.Arg41Lys	missense_variant	Exon 4 of 24	1	NM_001939.3	ENSP00000378635.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000562 AC: 1 AN: 178021 Hom.: 0 AF XY: 0.0000159 AC XY: 1 AN XY: 62923

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: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093401 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 359597

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 41 of the DRP2 protein (p.Arg41Lys). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with DRP2-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DRP2 protein function with a positive predictive value of 80%. 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	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0086	T;T;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.59	.;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.16	N;N;N
REVEL	Benign	0.082
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.96	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.063
MutPred		0.17		Gain of methylation at R41 (P = 0.012);Gain of methylation at R41 (P = 0.012);Gain of methylation at R41 (P = 0.012);
MVP		0.41
MPC		0.40
ClinPred		0.27	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.34

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: rs1254070988; hg19: chrX-100490853;