X-101231676-C-G

Variant names:

• chrX-101231676-C-G
• rs909100703
• NM_001939.3:c.29C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_001939.3(DRP2):​c.29C>G​(p.Pro10Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,209,041 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 3 hem.)
• Consequence: DRP2 NM_001939.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.62
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28131318).
• BS2: High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001939.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRP2	NM_001939.3	MANE Select	c.29C>G	p.Pro10Arg	missense	Exon 3 of 24	NP_001930.2	Q13474-1
	DRP2	NM_001171184.2		c.-117-4184C>G		intron	N/A	NP_001164655.1	Q13474-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRP2	ENST00000395209.8	TSL:1 MANE Select	c.29C>G	p.Pro10Arg	missense	Exon 3 of 24	ENSP00000378635.3	Q13474-1
	DRP2	ENST00000402866.5	TSL:5	c.29C>G	p.Pro10Arg	missense	Exon 3 of 24	ENSP00000385038.1	Q13474-1
	DRP2	ENST00000538510.1	TSL:2	c.29C>G	p.Pro10Arg	missense	Exon 1 of 22	ENSP00000441051.1	Q13474-1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111161 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183265 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000273 AC: 3 AN: 1097880 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363246

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.0000284 AC: 1 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841801

Other (OTH) AF: 0.0000217 AC: 1 AN: 46091

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111161 Hom.: 0 Cov.: 22 AF XY: 0.0000600 AC XY: 2 AN XY: 33347

African (AFR) AF: 0.00 AC: 0 AN: 30499

American (AMR) AF: 0.000191 AC: 2 AN: 10452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2595

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6061

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52974

Other (OTH) AF: 0.00 AC: 0 AN: 1483

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0073	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.58	P
Vest4		0.52
MutPred		0.27		Gain of MoRF binding (P = 0.0462)
MVP		0.60
MPC		0.48
ClinPred		0.33	T
GERP RS		5.8
PromoterAI		0.025	Neutral
Varity_R		0.24
gMVP		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs909100703; hg19: chrX-100486665;