chr8-38237554-C-T

Variant names:

• chr8-38237554-C-T
• rs1554512152
• NM_015214.3:c.428C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015214.3(DDHD2):​c.428C>T​(p.Ala143Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDHD2 NM_015214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD2	NM_015214.3	c.428C>T	p.Ala143Val	missense_variant	Exon 4 of 18	ENST00000397166.7	NP_056029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD2	ENST00000397166.7	c.428C>T	p.Ala143Val	missense_variant	Exon 4 of 18	2	NM_015214.3	ENSP00000380352.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 54 Uncertain:1

Sep 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with valine at codon 143 of the DDHD2 protein (p.Ala143Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DDHD2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T;.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.;M
PhyloP100		5.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D
Polyphen		0.38, 1.0	.;B;.;.;D;B
Vest4		0.34, 0.34
MutPred		0.49		Gain of catalytic residue at A143 (P = 0.0576);Gain of catalytic residue at A143 (P = 0.0576);.;.;Gain of catalytic residue at A143 (P = 0.0576);Gain of catalytic residue at A143 (P = 0.0576);
MVP		0.33
MPC		0.40
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.47
gMVP		0.60
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1554512152; hg19: chr8-38095072;