chrX-101231742-G-A

Position:

chrX-101231742-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The NM_001939.3(DRP2):c.95G>A(p.Arg32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,207,740 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 0 hom. 49 hem. )

Consequence

DRP2
NM_001939.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.37

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP6

Variant X-101231742-G-A is Benign according to our data. Variant chrX-101231742-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1335783.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 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 linkuse as main transcript	c.95G>A	p.Arg32Gln	missense_variant	3/24	ENST00000395209.8	NP_001930.2	Q13474-1A0A024RCH3
DRP2	XM_047441894.1 linkuse as main transcript	c.95G>A	p.Arg32Gln	missense_variant	2/23		XP_047297850.1
DRP2	XM_017029333.2 linkuse as main transcript	c.95G>A	p.Arg32Gln	missense_variant	3/23		XP_016884822.1
DRP2	NM_001171184.2 linkuse as main transcript	c.-117-4118G>A		intron_variant			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.95G>A	p.Arg32Gln	missense_variant	3/24	1	NM_001939.3	ENSP00000378635.3		Q13474-1

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

111137

Hom.:

Cov.:

AF XY:

0.0000599

AC XY:

AN XY:

33365

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:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000283

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000154

AC:

AN:

182193

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

66771

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000626

Gnomad NFE exome

AF:

0.000295

Gnomad OTH exome

AF:

0.000445

GnomAD4 exome

AF:

0.000154

AC:

169

AN:

1096603

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

361993

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000123

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000144

AC:

AN:

111137

Hom.:

Cov.:

AF XY:

0.0000599

AC XY:

AN XY:

33365

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:

0.000166

Gnomad4 NFE

AF:

0.000283

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DRP2: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 32 of the DRP2 protein (p.Arg32Gln). This variant is present in population databases (rs201882686, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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: 1335783). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

0.072

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0059

T;T;T

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.85

.;.;D

M_CAP

Benign

0.084

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Benign

0.34

PROVEAN

Benign

0.69

N;N;N

REVEL

Benign

0.041

Sift

Uncertain

0.012

D;D;D

Sift4G

Uncertain

0.046

D;D;D

Polyphen

0.18

B;B;B

Vest4

0.18

MVP

0.33

MPC

0.47

ClinPred

0.053

GERP RS

4.8

Varity_R

0.18

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: 22

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