8-38234399-G-T

Variant names:

• chr8-38234399-G-T
• rs141644282
• NM_015214.3:c.226G>T

Variant summary

Our verdict is Benign. The variant received -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. 10/14 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:4
• Conservation: PhyloP100: 1.12
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.094).
• 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 VariationId is 734414.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	NM_015214.3	MANE Select	c.226G>T	p.Gly76Cys	missense	Exon 3 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.226G>T	p.Gly76Cys	missense	Exon 3 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.226G>T	p.Gly76Cys	missense	Exon 3 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.226G>T	p.Gly76Cys	missense	Exon 3 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000529642.1	TSL:5	c.-63G>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000436444.1	E9PP45
	DDHD2	ENST00000853787.1		c.226G>T	p.Gly76Cys	missense	Exon 3 of 18	ENSP00000523846.1

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

GnomAD2 exomes AF: 0.00121 AC: 261 AN: 216346 AF XY: 0.000958

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 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

African (AFR) AF: 0.00769 AC: 240 AN: 31218

American (AMR) AF: 0.00205 AC: 66 AN: 32198

Ashkenazi Jewish (ASJ) AF: 0.00246 AC: 61 AN: 24774

East Asian (EAS) AF: 0.00 AC: 0 AN: 37998

South Asian (SAS) AF: 0.000102 AC: 8 AN: 78660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00337 AC: 19 AN: 5630

European-Non Finnish (NFE) AF: 0.000289 AC: 317 AN: 1098724

Other (OTH) AF: 0.00159 AC: 93 AN: 58584

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

African (AFR) AF: 0.0101 AC: 420 AN: 41512

American (AMR) AF: 0.00262 AC: 40 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67990

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.000537 Hom.: 4

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 54 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
ClinPred		0.019	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs141644282; hg19: chr8-38091917;