8-38234400-G-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.227G>A(p.Gly76Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,577,418 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G76C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (2 hom.)
• Consequence: DDHD2 NM_015214.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.22

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=0.0027008057).
• BP6: Variant 8-38234400-G-A is Benign according to our data. Variant chr8-38234400-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 701940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00338 (515/152166) while in subpopulation AFR AF= 0.0101 (420/41488). AF 95% confidence interval is 0.00932. There are 2 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDHD2	NM_015214.3	c.227G>A	p.Gly76Asp	missense_variant	3/18	ENST00000397166.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDHD2	ENST00000397166.7	c.227G>A	p.Gly76Asp	missense_variant	3/18	2	NM_015214.3	P1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152048 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00119 AC: 261 AN: 219684 Hom.: 2 AF XY: 0.000970 AC XY: 116 AN XY: 119628

Gnomad AFR exome AF: 0.00883

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000208

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000509

Gnomad OTH exome AF: 0.000967

GnomAD4 exome AF: 0.000575 AC: 819 AN: 1425252 Hom.: 2 Cov.: 30 AF XY: 0.000528 AC XY: 374 AN XY: 708308

Gnomad4 AFR exome AF: 0.00761

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.00244

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152166 Hom.: 2 Cov.: 32 AF XY: 0.00331 AC XY: 246 AN XY: 74402

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00131 Hom.: 3

Bravo AF: 0.00384

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00141 AC: 171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 54 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

DDHD2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	12
Dann	Benign	0.29
DEOGEN2	Benign	0.0030	T;T;T;T;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.18	T;.;T;T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.0027	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.71	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	3.1	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;B;B
Vest4		0.11, 0.11
MVP		0.12
MPC		0.19
ClinPred		0.0040	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs150361106; hg19: chr8-38091918;