rs148536791

chr8-38253711-T-A

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: 7.94

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 473072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38253711-T-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDHD2	NM_015214.3	c.2047T>A	p.Cys683Ser	missense_variant	16/18	ENST00000397166.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDHD2	ENST00000397166.7	c.2047T>A	p.Cys683Ser	missense_variant	16/18	2	NM_015214.3	P1

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

GnomAD3 exomes AF: 0.00261 AC: 653 AN: 250586 Hom.: 2 AF XY: 0.00266 AC XY: 360 AN XY: 135468

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 SAS 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

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000449

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00219

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

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.000947

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2017

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

DDHD2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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;T;.;D;D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.3	D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D;T
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		0.87	P;P;.;.;.
Vest4		0.81
MutPred		0.66		Gain of disorder (P = 0.0086);Gain of disorder (P = 0.0086);.;.;.;
MVP		0.61
MPC		0.71
ClinPred		0.062	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs148536791; hg19: chr8-38111229;