8-38234399-G-A

Variant names:

• chr8-38234399-G-A
• rs141644282
• NM_015214.3:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015214.3(DDHD2):​c.226G>A​(p.Gly76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,420,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict 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. G76C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: DDHD2 NM_015214.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 6 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: 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 (REVEL=0.057).

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.226G>A	p.Gly76Ser	missense	Exon 3 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.226G>A	p.Gly76Ser	missense	Exon 3 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.226G>A	p.Gly76Ser	missense	Exon 3 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.226G>A	p.Gly76Ser	missense	Exon 3 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.226G>A	p.Gly76Ser	missense	Exon 3 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.226G>A	p.Gly76Ser	missense	Exon 3 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000462 AC: 1 AN: 216346 AF XY: 0.00000848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000197 AC: 28 AN: 1420822 Hom.: 0 Cov.: 30 AF XY: 0.0000227 AC XY: 16 AN XY: 705868

African (AFR) AF: 0.00 AC: 0 AN: 31228

American (AMR) AF: 0.00 AC: 0 AN: 32200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24774

East Asian (EAS) AF: 0.00 AC: 0 AN: 37998

South Asian (SAS) AF: 0.00 AC: 0 AN: 78660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.0000255 AC: 28 AN: 1098734

Other (OTH) AF: 0.00 AC: 0 AN: 58586

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0029	T
PhyloP100		1.1
ClinPred		0.18	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs141644282; hg19: chr8-38091917; COSMIC: COSV68157383;