8-38234399-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_015214.3(DDHD2):c.226G>T(p.Gly76Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,572,976 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G76Y) 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.12

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.113641).
• BP6: Variant 8-38234399-G-T is Benign according to our data. Variant chr8-38234399-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 734414.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00337 (513/152178) while in subpopulation AFR AF= 0.0101 (420/41512). AF 95% confidence interval is 0.00932. There are 2 homozygotes in gnomad4. There are 244 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.226G>T	p.Gly76Cys	missense_variant	3/18	ENST00000397166.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDHD2	ENST00000397166.7	c.226G>T	p.Gly76Cys	missense_variant	3/18	2	NM_015214.3	P1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152060 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00121 AC: 261 AN: 216346 Hom.: 2 AF XY: 0.000958 AC XY: 113 AN XY: 117930

Gnomad AFR exome AF: 0.00889

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00275

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000566 AC: 804 AN: 1420798 Hom.: 2 Cov.: 30 AF XY: 0.000513 AC XY: 362 AN XY: 705860

Gnomad4 AFR exome AF: 0.00769

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00246

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000289

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152178 Hom.: 2 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74418

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.000616 Hom.: 3

Bravo AF: 0.00384

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00137 AC: 167

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.226G>T (p.G76C) alteration is located in exon 3 (coding exon 2) of the DDHD2 gene. This alteration results from a G to T substitution at nucleotide position 226, causing the glycine (G) at amino acid position 76 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 54 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

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	0.097
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.086
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0064	T
MutationTaster	Benign	0.82	D;D
ClinPred		0.019	T
GERP RS		4.9
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

Publications

LitVar

Other links and lift over

dbSNP: rs141644282; hg19: chr8-38091917;