8-38247755-C-T

Variant names:

• chr8-38247755-C-T
• rs142190071
• NM_015214.3:c.1168C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015214.3(DDHD2):​c.1168C>T​(p.Leu390Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,574,170 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: DDHD2 NM_015214.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.130
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-38247755-C-T is Benign according to our data. Variant chr8-38247755-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0029 (442/152292) while in subpopulation AFR AF = 0.0103 (430/41566). AF 95% confidence interval is 0.00954. There are 1 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.1168C>T	p.Leu390Leu	synonymous	Exon 10 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.1168C>T	p.Leu390Leu	synonymous	Exon 10 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.1168C>T	p.Leu390Leu	synonymous	Exon 10 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.1168C>T	p.Leu390Leu	synonymous	Exon 10 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.1168C>T	p.Leu390Leu	synonymous	Exon 10 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.1168C>T	p.Leu390Leu	synonymous	Exon 10 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152174 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000623 AC: 145 AN: 232770 AF XY: 0.000452

Gnomad AFR exome AF: 0.00902

Gnomad AMR exome AF: 0.000103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.000262 AC: 373 AN: 1421878 Hom.: 3 Cov.: 26 AF XY: 0.000219 AC XY: 155 AN XY: 708456

African (AFR) AF: 0.0102 AC: 322 AN: 31660

American (AMR) AF: 0.000357 AC: 14 AN: 39240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25360

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1087990

Other (OTH) AF: 0.000526 AC: 31 AN: 58898

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152292 Hom.: 1 Cov.: 31 AF XY: 0.00286 AC XY: 213 AN XY: 74470

African (AFR) AF: 0.0103 AC: 430 AN: 41566

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00326

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 54 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.38
DANN	Benign	0.45
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs142190071; hg19: chr8-38105273;