Genetic Variant DDAH2:c.-589A>G (chr6-31730575-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000375792.7(DDAH2):c.-589A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 484,664 control chromosomes in the GnomAD database, including 180,895 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.88 ( 59013 hom., cov: 32)

Exomes 𝑓: 0.85 ( 121882 hom. )

Consequence

DDAH2
ENST00000375792.7 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.62

Publications

26 publications found

Variant links:

Genes affected

DDAH2 (HGNC:2716): (DDAH family member 2, ADMA-independent) This gene encodes a dimethylarginine dimethylaminohydrolase. The encoded enzyme functions in nitric oxide generation by regulating the cellular concentrations of methylarginines, which in turn inhibit nitric oxide synthase activity. The protein may be localized to the mitochondria. Alternative splicing resulting in multiple transcript variants. [provided by RefSeq, Dec 2014]

DDAH2 links:

CLIC1 (HGNC:2062): (chloride intracellular channel 1) Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 1 is a member of the p64 family; the protein localizes principally to the cell nucleus and exhibits both nuclear and plasma membrane chloride ion channel activity. [provided by RefSeq, Jul 2008]

CLIC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CLIC1	NM_001288.6 link	c.*267A>G	downstream_gene_variant	ENST00000375784.8	NP_001279.2
CLIC1	NM_001287593.1 link	c.*267A>G	downstream_gene_variant		NP_001274522.1
CLIC1	NM_001287594.3 link	c.*267A>G	downstream_gene_variant		NP_001274523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC1	ENST00000375784.8 link	c.*267A>G		downstream_gene_variant		1	NM_001288.6	ENSP00000364940.3

Frequencies

GnomAD3 genomes

AF:

0.878

AC:

133535

AN:

152092

Hom.:

58952

Cov.:

show subpopulations

Gnomad AFR

AF:

0.967

Gnomad AMI

AF:

0.774

Gnomad AMR

AF:

0.914

Gnomad ASJ

AF:

0.935

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.894

Gnomad FIN

AF:

0.845

Gnomad MID

AF:

0.946

Gnomad NFE

AF:

0.824

Gnomad OTH

AF:

0.904

GnomAD4 exome

AF:

0.854

AC:

283862

AN:

332454

Hom.:

121882

Cov.:

AF XY:

0.857

AC XY:

148428

AN XY:

173158

show subpopulations

African (AFR)

AF:

0.967

AC:

9718

AN:

10048

American (AMR)

AF:

0.922

AC:

11876

AN:

12880

Ashkenazi Jewish (ASJ)

AF:

0.933

AC:

10328

AN:

11070

East Asian (EAS)

AF:

0.874

AC:

20910

AN:

23920

South Asian (SAS)

AF:

0.904

AC:

25915

AN:

28656

European-Finnish (FIN)

AF:

0.838

AC:

18267

AN:

21798

Middle Eastern (MID)

AF:

0.926

AC:

1439

AN:

1554

European-Non Finnish (NFE)

AF:

0.831

AC:

167903

AN:

202160

Other (OTH)

AF:

0.859

AC:

17506

AN:

20368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1860

3720

5581

7441

9301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

682

1364

2046

2728

3410

<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:

0.878

AC:

133656

AN:

152210

Hom.:

59013

Cov.:

AF XY:

0.879

AC XY:

65390

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.967

AC:

40184

AN:

41544

American (AMR)

AF:

0.914

AC:

13974

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.935

AC:

3243

AN:

3470

East Asian (EAS)

AF:

0.785

AC:

4058

AN:

5168

South Asian (SAS)

AF:

0.895

AC:

4320

AN:

4828

European-Finnish (FIN)

AF:

0.845

AC:

8954

AN:

10596

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.824

AC:

56036

AN:

67996

Other (OTH)

AF:

0.903

AC:

1907

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

822

1645

2467

3290

4112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.851

Hom.:

108206

Bravo

AF:

0.887

Asia WGS

AF:

0.897

AC:

3121

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.12

(source)

DANN

Benign

0.63

PhyloP100

-3.6

PromoterAI

-0.028

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over