X-101235915-G-A

Position:

chrX-101235915-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001939.3(DRP2):c.173G>A(p.Cys58Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,210,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000062 ( 0 hom. 25 hem. )

Consequence

DRP2
NM_001939.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.49

Variant links:

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]

DRP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19230258).

BS2

High Hemizygotes in GnomAdExome4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRP2	NM_001939.3 linkuse as main transcript	c.173G>A	p.Cys58Tyr	missense_variant	4/24	ENST00000395209.8	NP_001930.2	Q13474-1A0A024RCH3
DRP2	XM_047441894.1 linkuse as main transcript	c.173G>A	p.Cys58Tyr	missense_variant	3/23		XP_047297850.1
DRP2	XM_017029333.2 linkuse as main transcript	c.173G>A	p.Cys58Tyr	missense_variant	4/23		XP_016884822.1
DRP2	NM_001171184.2 linkuse as main transcript	c.-62G>A		5_prime_UTR_variant	2/22		NP_001164655.1	Q13474-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRP2	ENST00000395209.8 linkuse as main transcript	c.173G>A	p.Cys58Tyr	missense_variant	4/24	1	NM_001939.3	ENSP00000378635.3		Q13474-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112309

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34467

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183143

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67593

show subpopulations

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:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000619

AC:

AN:

1097939

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

363303

show subpopulations

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:

0.0000760

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112309

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34467

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.173G>A (p.C58Y) alteration is located in exon 4 (coding exon 2) of the DRP2 gene. This alteration results from a G to A substitution at nucleotide position 173, causing the cysteine (C) at amino acid position 58 to be replaced by a tyrosine (Y). 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

Oct 30, 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. This variant has not been reported in the literature in individuals affected with DRP2-related conditions. This variant is present in population databases (rs772399679, gnomAD 0.006%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 58 of the DRP2 protein (p.Cys58Tyr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.65

.;.;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.0

B;B;B

Vest4

0.15

MVP

0.57

MPC

0.68

ClinPred

0.22

GERP RS

5.2

Varity_R

0.58

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over