8-38253711-T-A

Variant names:

• chr8-38253711-T-A
• rs148536791
• NM_015214.3:c.2047T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015214.3(DDHD2):​c.2047T>A​(p.Cys683Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,460 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: DDHD2 NM_015214.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.94
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020032167).
• BP6: Variant 8-38253711-T-A is Benign according to our data. Variant chr8-38253711-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473072.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 = 0.00242 (369/152364) while in subpopulation NFE AF = 0.00284 (193/68034). AF 95% confidence interval is 0.00251. There are 1 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	NM_015214.3	MANE Select	c.2047T>A	p.Cys683Ser	missense	Exon 16 of 18	NP_056029.2
	DDHD2	NM_001164232.2		c.2047T>A	p.Cys683Ser	missense	Exon 16 of 18	NP_001157704.1
	DDHD2	NM_001362911.2		c.2047T>A	p.Cys683Ser	missense	Exon 16 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.2047T>A	p.Cys683Ser	missense	Exon 16 of 18	ENSP00000380352.2
	DDHD2	ENST00000520272.6	TSL:2	c.2047T>A	p.Cys683Ser	missense	Exon 16 of 18	ENSP00000429932.2
	DDHD2	ENST00000517385.5	TSL:2	c.904T>A	p.Cys302Ser	missense	Exon 7 of 9	ENSP00000429017.1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 369 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00261 AC: 653 AN: 250586 AF XY: 0.00266

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00271 AC: 3954 AN: 1461096 Hom.: 8 Cov.: 31 AF XY: 0.00267 AC XY: 1939 AN XY: 726874

African (AFR) AF: 0.000299 AC: 10 AN: 33438

American (AMR) AF: 0.000449 AC: 20 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.0119 AC: 638 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00278 AC: 3085 AN: 1111638

Other (OTH) AF: 0.00219 AC: 132 AN: 60362

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74502

African (AFR) AF: 0.000769 AC: 32 AN: 41598

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68034

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00254 Hom.: 1

Bravo AF: 0.00143

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00297 AC: 360

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DDHD2: BS1, BS2

not specified Benign:1

Nov 21, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Hereditary spastic paraplegia 54 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spastic paraplegia Benign:1

May 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.87	P
Vest4		0.81
MutPred		0.66		Gain of disorder (P = 0.0086)
MVP		0.61
MPC		0.71
ClinPred		0.062	T
GERP RS		5.1
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.63
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148536791; hg19: chr8-38111229; COSMIC: COSV106114201; COSMIC: COSV106114201;