rs767497993

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_015214.3(DDHD2):c.725G>A(p.Arg242His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000303 in 1,585,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DDHD2
NM_015214.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.96

Publications

3 publications found

Variant links:

Genes affected

DDHD2 (HGNC:29106): (DDHD domain containing 2) This gene encodes a phospholipase enzyme containing sterile-alpha-motif (SAM), WWE, and DDHD domains. This protein participates in membrane trafficking between the endoplastic reticulum and the Golgi body. Mutations in this gene can cause autosomal recessive spastic paraplegia 54. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

DDHD2 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 54
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

DDHD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-38242261-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 988994.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 8-38242262-G-A is Pathogenic according to our data. Variant chr8-38242262-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540290.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD2	NM_015214.3 link	c.725G>A	p.Arg242His	missense_variant	Exon 7 of 18	ENST00000397166.7	NP_056029.2	O94830-1B3KPM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD2	ENST00000397166.7 link	c.725G>A	p.Arg242His	missense_variant	Exon 7 of 18	2	NM_015214.3	ENSP00000380352.2		O94830-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152032

Hom.:

Cov.:

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000886

AC:

AN:

225626

AF XY:

0.00000816

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:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000307

AC:

AN:

1433166

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

712534

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31504

American (AMR)

AF:

0.0000576

AC:

AN:

34722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24928

East Asian (EAS)

AF:

0.00

AC:

AN:

39380

South Asian (SAS)

AF:

0.00

AC:

AN:

80910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000344

AC:

AN:

1103482

Other (OTH)

AF:

0.0000505

AC:

AN:

59348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.0000263

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 54

Pathogenic:1Uncertain:1

May 14, 2022

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 histidine, which is basic and polar, at codon 242 of the DDHD2 protein (p.Arg242His). This variant is present in population databases (rs767497993, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DDHD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 540290). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.725G>A (p.R242H) alteration is located in exon 7 (coding exon 6) of the DDHD2 gene. This alteration results from a G to A substitution at nucleotide position 725, causing the arginine (R) at amino acid position 242 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/225626) total alleles studied. The highest observed frequency was 0.002% (2/107380) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.46

.;T;D

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.8

M;.;M

PhyloP100

8.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.018

D;D;D

Polyphen

0.81

P;.;P

Vest4

0.81

MutPred

0.80

Loss of MoRF binding (P = 0.0777);.;Loss of MoRF binding (P = 0.0777);

MVP

0.66

MPC

0.20

ClinPred

0.97

GERP RS

4.6

Varity_R

0.27

gMVP

0.90

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.45

Position offset: 26

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over