rs148664622

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015214.3(DDHD2):c.1127A>G(p.Asp376Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,489,866 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0043 ( 10 hom. )

Consequence

DDHD2
NM_015214.3 missense, splice_region

Scores

Splicing: ADA: 0.00008901

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.606

Publications

9 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024392903).

BP6

Variant 8-38247714-A-G is Benign according to our data. Variant chr8-38247714-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 210838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0029 (442/152312) while in subpopulation NFE AF = 0.00494 (336/68026). AF 95% confidence interval is 0.0045. There are 2 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD2	NM_015214.3 link	c.1127A>G	p.Asp376Gly	missense_variant, splice_region_variant	Exon 10 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.1127A>G	p.Asp376Gly	missense_variant, splice_region_variant	Exon 10 of 18	2	NM_015214.3	ENSP00000380352.2		O94830-1

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

442

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00293

AC:

550

AN:

187908

AF XY:

0.00297

show subpopulations

Gnomad AFR exome

AF:

0.000605

Gnomad AMR exome

AF:

0.00178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00470

Gnomad OTH exome

AF:

0.00254

GnomAD4 exome

AF:

0.00429

AC:

5740

AN:

1337554

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

2810

AN XY:

665698

show subpopulations

African (AFR)

AF:

0.000677

AC:

AN:

28060

American (AMR)

AF:

0.00220

AC:

AN:

25474

Ashkenazi Jewish (ASJ)

AF:

0.0000896

AC:

AN:

22320

East Asian (EAS)

AF:

0.00

AC:

AN:

35970

South Asian (SAS)

AF:

0.0000141

AC:

AN:

70692

European-Finnish (FIN)

AF:

0.00322

AC:

164

AN:

50998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

0.00503

AC:

5251

AN:

1043870

Other (OTH)

AF:

0.00450

AC:

247

AN:

54874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

219

437

656

874

1093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00290

AC:

442

AN:

152312

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41586

American (AMR)

AF:

0.00157

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00494

AC:

336

AN:

68026

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00382

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00478

AC:

ExAC

AF:

0.00272

AC:

330

Asia WGS

AF:

0.000579

AC:

AN:

3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 54

Benign:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DDHD2: BP4, BS2 -

Feb 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DDHD2-related disorder

Benign:1

Nov 21, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Mar 05, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0096

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.55

.;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.44

N;N

PhyloP100

0.61

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.066

Sift

Benign

0.27

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0

B;B

Vest4

0.082

MVP

0.040

MPC

0.19

ClinPred

0.0029

GERP RS

-6.1

Varity_R

0.038

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000089

dbscSNV1_RF

Benign

0.054

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over