8-38233052-C-T

Position:

• chr8-38233052-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015214.3(DDHD2):​c.58C>T​(p.Pro20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 0.987

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05936578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDHD2	NM_015214.3	c.58C>T	p.Pro20Ser	missense_variant	2/18	ENST00000397166.7	NP_056029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDHD2	ENST00000397166.7	c.58C>T	p.Pro20Ser	missense_variant	2/18	2	NM_015214.3	ENSP00000380352.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 54 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with DDHD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 20 of the DDHD2 protein (p.Pro20Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.023	T;T;T;T;.;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.68	T;.;T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.059	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	.;N;.;.;.;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	N;N;N;D;D;N
REVEL	Benign	0.082
Sift	Benign	0.33	T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;.;.;B;B
Vest4		0.10, 0.11
MutPred		0.14		Gain of phosphorylation at P20 (P = 0.0206);Gain of phosphorylation at P20 (P = 0.0206);Gain of phosphorylation at P20 (P = 0.0206);Gain of phosphorylation at P20 (P = 0.0206);Gain of phosphorylation at P20 (P = 0.0206);Gain of phosphorylation at P20 (P = 0.0206);
MVP		0.14
MPC		0.14
ClinPred		0.15	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs1804416698; hg19: chr8-38090570;