chr8-38245757-A-C

Variant names:

• chr8-38245757-A-C
• rs148904419
• NM_015214.3:c.864A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_015214.3(DDHD2):​c.864A>C​(p.Ile288Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,614,114 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: DDHD2 NM_015214.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.86
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-38245757-A-C is Benign according to our data. Variant chr8-38245757-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 473076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000368 (56/152356) while in subpopulation NFE AF = 0.000617 (42/68038). AF 95% confidence interval is 0.000469. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.864A>C	p.Ile288Ile	synonymous	Exon 8 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.864A>C	p.Ile288Ile	synonymous	Exon 8 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.864A>C	p.Ile288Ile	synonymous	Exon 8 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.864A>C	p.Ile288Ile	synonymous	Exon 8 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.864A>C	p.Ile288Ile	synonymous	Exon 8 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.864A>C	p.Ile288Ile	synonymous	Exon 8 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000322 AC: 81 AN: 251288 AF XY: 0.000317

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000459 AC: 671 AN: 1461758 Hom.: 1 Cov.: 32 AF XY: 0.000472 AC XY: 343 AN XY: 727170

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53326

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000508 AC: 565 AN: 1111982

Other (OTH) AF: 0.000513 AC: 31 AN: 60390

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74502

African (AFR) AF: 0.000144 AC: 6 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000351

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.4
DANN	Benign	0.64
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs148904419; hg19: chr8-38103275;