Genetic Variant NM_015214.3:c.227G>A (chr8-38234400-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 16/22 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.22

Publications

5 publications found

Variant links:

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), Orphanet, G2P

DDHD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDHD2	NM_015214.3	MANE Select	c.227G>A	p.Gly76Asp	missense	Exon 3 of 18	NP_056029.2	O94830-1
DDHD2	NM_001164232.2		c.227G>A	p.Gly76Asp	missense	Exon 3 of 18	NP_001157704.1	O94830-1
DDHD2	NM_001362911.2		c.227G>A	p.Gly76Asp	missense	Exon 3 of 18	NP_001349840.1	O94830-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDHD2	ENST00000397166.7	TSL:2 MANE Select	c.227G>A	p.Gly76Asp	missense	Exon 3 of 18	ENSP00000380352.2	O94830-1
DDHD2	ENST00000853787.1		c.227G>A	p.Gly76Asp	missense	Exon 3 of 18	ENSP00000523846.1
DDHD2	ENST00000520272.6	TSL:2	c.227G>A	p.Gly76Asp	missense	Exon 3 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152048

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00119

AC:

261

AN:

219684

AF XY:

0.000970

show subpopulations

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 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.:

Cov.:

AF XY:

0.000528

AC XY:

374

AN XY:

708308

show subpopulations

African (AFR)

AF:

0.00761

AC:

239

AN:

31424

American (AMR)

AF:

0.00194

AC:

AN:

33442

Ashkenazi Jewish (ASJ)

AF:

0.00244

AC:

AN:

24974

East Asian (EAS)

AF:

0.00

AC:

AN:

38144

South Asian (SAS)

AF:

0.000290

AC:

AN:

79272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.00337

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.000290

AC:

319

AN:

1100508

Other (OTH)

AF:

0.00158

AC:

AN:

58806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00338

AC:

515

AN:

152166

Hom.:

Cov.:

AF XY:

0.00331

AC XY:

246

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0101

AC:

420

AN:

41488

American (AMR)

AF:

0.00262

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

67998

Other (OTH)

AF:

0.00569

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00384

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00141

AC:

171

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 54 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0030

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.18

M_CAP

Benign

0.0028

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.29

PhyloP100

1.2

PrimateAI

Benign

0.40

PROVEAN

Benign

3.1

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MVP

0.12

MPC

0.19

ClinPred

0.0040

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.045

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over