Genetic Variant DDHD2:p.Pro210Ser (chr8-38240280-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015214.3(DDHD2):c.628C>T(p.Pro210Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000083 in 1,446,184 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P210T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

DDHD2
NM_015214.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.61

Publications

0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

DDHD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22751126).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDHD2	NM_015214.3	MANE Select	c.628C>T	p.Pro210Ser	missense	Exon 6 of 18	NP_056029.2	O94830-1
DDHD2	NM_001164232.2		c.628C>T	p.Pro210Ser	missense	Exon 6 of 18	NP_001157704.1	O94830-1
DDHD2	NM_001362911.2		c.628C>T	p.Pro210Ser	missense	Exon 6 of 18	NP_001349840.1	O94830-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDHD2	ENST00000397166.7	TSL:2 MANE Select	c.628C>T	p.Pro210Ser	missense	Exon 6 of 18	ENSP00000380352.2	O94830-1
DDHD2	ENST00000853787.1		c.628C>T	p.Pro210Ser	missense	Exon 6 of 18	ENSP00000523846.1
DDHD2	ENST00000520272.6	TSL:2	c.628C>T	p.Pro210Ser	missense	Exon 6 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000830

AC:

AN:

1446184

Hom.:

Cov.:

AF XY:

0.00000695

AC XY:

AN XY:

719330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33214

American (AMR)

AF:

0.00

AC:

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25844

East Asian (EAS)

AF:

0.00

AC:

AN:

39498

South Asian (SAS)

AF:

0.00

AC:

AN:

84886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1099872

Other (OTH)

AF:

0.00

AC:

AN:

59666

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0087

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

3.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.15

Sift

Benign

0.51

Sift4G

Benign

0.24

Polyphen

0.57

Vest4

0.29

MutPred

0.48

Loss of catalytic residue at L211 (P = 0.2472)

MVP

0.26

MPC

0.64

ClinPred

0.99

GERP RS

5.5

PromoterAI

0.0020

Neutral

(source)

Varity_R

0.26

gMVP

0.58

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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