NM_015214.3:c.725G>T

Variant names:

• chr8-38242262-G-T
• rs767497993
• NM_015214.3:c.725G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_015214.3(DDHD2):​c.725G>T​(p.Arg242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R242C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DDHD2 NM_015214.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-38242261-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 988994.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	NM_015214.3	MANE Select	c.725G>T	p.Arg242Leu	missense	Exon 7 of 18	NP_056029.2
	DDHD2	NM_001164232.2		c.725G>T	p.Arg242Leu	missense	Exon 7 of 18	NP_001157704.1
	DDHD2	NM_001362911.2		c.725G>T	p.Arg242Leu	missense	Exon 7 of 18	NP_001349840.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	ENST00000397166.7	TSL:2 MANE Select	c.725G>T	p.Arg242Leu	missense	Exon 7 of 18	ENSP00000380352.2
	DDHD2	ENST00000520272.6	TSL:2	c.725G>T	p.Arg242Leu	missense	Exon 7 of 18	ENSP00000429932.2
	DDHD2	ENST00000532222.5	TSL:5	c.635G>T	p.Arg212Leu	missense	Exon 6 of 6	ENSP00000433578.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 712534

African (AFR) AF: 0.00 AC: 0 AN: 31504

American (AMR) AF: 0.00 AC: 0 AN: 34722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 80910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103482

Other (OTH) AF: 0.0000168 AC: 1 AN: 59348

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.87
MutPred		0.75		Loss of catalytic residue at R242 (P = 0.021)
MVP		0.85
MPC		0.46
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.94
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 26

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

Other links and lift over

dbSNP: rs767497993; hg19: chr8-38099780;