Genetic Variant DRP2:c.118-3C>T (chrX-101235857-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001939.3(DRP2):c.118-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,086,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.000034 ( 0 hom. 13 hem. )

Consequence

DRP2
NM_001939.3 splice_region, intron

Scores

Splicing: ADA: 0.003123

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

DRP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BS2

High Hemizygotes in GnomAdExome4 at 13 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.118-3C>T		splice_region intron	N/A	NP_001930.2	Q13474-1
	DRP2	NM_001171184.2		c.-117-3C>T		splice_region intron	N/A	NP_001164655.1	Q13474-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DRP2	ENST00000395209.8	TSL:1 MANE Select	c.118-3C>T	splice_region intron	N/A	ENSP00000378635.3	Q13474-1
DRP2	ENST00000402866.5	TSL:5	c.118-3C>T	splice_region intron	N/A	ENSP00000385038.1	Q13474-1
DRP2	ENST00000538510.1	TSL:2	c.118-3C>T	splice_region intron	N/A	ENSP00000441051.1	Q13474-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000576

AC:

AN:

173483

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000341

AC:

AN:

1086585

Hom.:

Cov.:

AF XY:

0.0000367

AC XY:

AN XY:

354495

show subpopulations

African (AFR)

AF:

0.0000385

AC:

AN:

25981

American (AMR)

AF:

0.00

AC:

AN:

33735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18942

East Asian (EAS)

AF:

0.00

AC:

AN:

29965

South Asian (SAS)

AF:

0.00

AC:

AN:

52487

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40367

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3498

European-Non Finnish (NFE)

AF:

0.0000431

AC:

AN:

836083

Other (OTH)

AF:

0.00

AC:

AN:

45527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0031

dbscSNV1_RF

Benign

0.050

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over