chr8-38252245-C-T

Variant names:

• chr8-38252245-C-T
• rs139004425
• NM_015214.3:c.1575C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6 BP7 BS1

The NM_015214.3(DDHD2):​c.1575C>T​(p.Tyr525Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DDHD2 NM_015214.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.13
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.231).
• BP6: Variant 8-38252245-C-T is Benign according to our data. Variant chr8-38252245-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 507257.
• BP7: Synonymous conserved (PhyloP=2.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000145 (212/1461782) while in subpopulation MID AF = 0.00191 (11/5768). AF 95% confidence interval is 0.00107. There are 1 homozygotes in GnomAdExome4. There are 116 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1575C>T	p.Tyr525Tyr	synonymous	Exon 13 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.1575C>T	p.Tyr525Tyr	synonymous	Exon 13 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.1575C>T	p.Tyr525Tyr	synonymous	Exon 13 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.1575C>T	p.Tyr525Tyr	synonymous	Exon 13 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.1599C>T	p.Tyr533Tyr	synonymous	Exon 13 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.1575C>T	p.Tyr525Tyr	synonymous	Exon 13 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251216 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1461782 Hom.: 1 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 727176

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00455 AC: 119 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86224

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111978

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000181

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 54 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.5
DANN	Benign	0.47
PhyloP100		2.1
PromoterAI		-0.018	Neutral
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139004425; hg19: chr8-38109763;