NM_015214.3:c.94_101dupGATGCTGG

Variant names:

• chr8-38233086-T-TGGATGCTG
• rs1554510884
• NM_015214.3:c.94_101dupGATGCTGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015214.3(DDHD2):​c.94_101dupGATGCTGG​(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 (★). Variant results in nonsense mediated mRNA decay.

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 523988.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	NM_015214.3	MANE Select	c.94_101dupGATGCTGG	p.Ser35MetfsTer18	frameshift	Exon 2 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.94_101dupGATGCTGG	p.Ser35MetfsTer18	frameshift	Exon 2 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.94_101dupGATGCTGG	p.Ser35MetfsTer18	frameshift	Exon 2 of 18	NP_001349840.1	O94830-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	ENST00000397166.7	TSL:2 MANE Select	c.94_101dupGATGCTGG	p.Ser35MetfsTer18	frameshift	Exon 2 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.94_101dupGATGCTGG	p.Ser35MetfsTer18	frameshift	Exon 2 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.94_101dupGATGCTGG	p.Ser35MetfsTer18	frameshift	Exon 2 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554510884; hg19: chr8-38090604;