rs149994413

Variant names:

• chr8-38238145-G-A
• rs149994413
• NM_015214.3:c.558G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS1

The NM_015214.3(DDHD2):​c.558G>A​(p.Thr186Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,613,854 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 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: DDHD2 NM_015214.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.27
• Publications: 2 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 -11 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 8-38238145-G-A is Benign according to our data. Variant chr8-38238145-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 385430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000224 (328/1461632) while in subpopulation AMR AF = 0.000784 (35/44666). AF 95% confidence interval is 0.000578. There are 1 homozygotes in GnomAdExome4. There are 160 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. 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.558G>A	p.Thr186Thr	synonymous	Exon 5 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.558G>A	p.Thr186Thr	synonymous	Exon 5 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.558G>A	p.Thr186Thr	synonymous	Exon 5 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.558G>A	p.Thr186Thr	synonymous	Exon 5 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.558G>A	p.Thr186Thr	synonymous	Exon 5 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.558G>A	p.Thr186Thr	synonymous	Exon 5 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000482 AC: 121 AN: 251088 AF XY: 0.000391

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000224 AC: 328 AN: 1461632 Hom.: 1 Cov.: 32 AF XY: 0.000220 AC XY: 160 AN XY: 727110

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.000784 AC: 35 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00639 AC: 167 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000881 AC: 98 AN: 1111934

Other (OTH) AF: 0.000447 AC: 27 AN: 60378

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74370

African (AFR) AF: 0.000121 AC: 5 AN: 41456

American (AMR) AF: 0.000393 AC: 6 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

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

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.000321

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

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	-0.88
CADD	Benign	16
DANN	Benign	0.53
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: 2

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

Other links and lift over

dbSNP: rs149994413; hg19: chr8-38095663;