8-38233086-T-TGGATGCTG

Position:

• chr8-38233086-T-TGGATGCTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015214.3(DDHD2):​c.94_101dup​(p.Ser35MetfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDHD2 NM_015214.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-38233086-T-TGGATGCTG is Pathogenic according to our data. Variant chr8-38233086-T-TGGATGCTG is described in ClinVar as [Pathogenic]. Clinvar id is 523988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDHD2	NM_015214.3	c.94_101dup	p.Ser35MetfsTer18	frameshift_variant	2/18	ENST00000397166.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDHD2	ENST00000397166.7	c.94_101dup	p.Ser35MetfsTer18	frameshift_variant	2/18	2	NM_015214.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2018

The c.94_101dupGATGCTGG variant in the DDHD2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.94_101dupGATGCTGG variant causes a frameshift starting with codon Serine 35, changes this amino acid to a Methionine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ser35MetfsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.94_101dupGATGCTGG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.94_101dupGATGCTGG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554510884; hg19: chr8-38090604;