rs6263

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001082971.2(DDC):c.649A>G(p.Met217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,614,074 control chromosomes in the GnomAD database, including 590 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 Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 100 hom., cov: 32)

Exomes 𝑓: 0.022 ( 490 hom. )

Consequence

DDC
NM_001082971.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.03

Publications

15 publications found

Variant links:

Genes affected

DDC (HGNC:2719): (dopa decarboxylase) The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2011]

DDC Gene-Disease associations (from GenCC):

aromatic L-amino acid decarboxylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

DDC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.40928 (below the threshold of 3.09). Trascript score misZ: 1.0771 (below the threshold of 3.09). GenCC associations: The gene is linked to aromatic L-amino acid decarboxylase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021415353).

BP6

Variant 7-50528202-T-C is Benign according to our data. Variant chr7-50528202-T-C is described in ClinVar as Benign. ClinVar VariationId is 360434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDC	NM_001082971.2 link	c.649A>G	p.Met217Val	missense_variant	Exon 6 of 15	ENST00000444124.7	NP_001076440.2	P20711-1Q53Y41A0A0S2Z3N4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7 link	c.649A>G	p.Met217Val	missense_variant	Exon 6 of 15	1	NM_001082971.2	ENSP00000403644.2		P20711-1

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4535

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.0786

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0673

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.0270

AC:

6792

AN:

251456

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.0407

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0280

Gnomad EAS exome

AF:

0.0688

Gnomad FIN exome

AF:

0.0646

Gnomad NFE exome

AF:

0.0188

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0217

AC:

31756

AN:

1461764

Hom.:

490

Cov.:

AF XY:

0.0213

AC XY:

15486

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0404

AC:

1354

AN:

33480

American (AMR)

AF:

0.0152

AC:

678

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

744

AN:

26136

East Asian (EAS)

AF:

0.0732

AC:

2905

AN:

39698

South Asian (SAS)

AF:

0.0129

AC:

1115

AN:

86248

European-Finnish (FIN)

AF:

0.0622

AC:

3325

AN:

53420

Middle Eastern (MID)

AF:

0.00880

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.0182

AC:

20203

AN:

1111998

Other (OTH)

AF:

0.0229

AC:

1382

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1781

3561

5342

7122

8903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.0298

AC:

4545

AN:

152310

Hom.:

100

Cov.:

AF XY:

0.0315

AC XY:

2344

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0418

AC:

1736

AN:

41562

American (AMR)

AF:

0.0135

AC:

206

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

107

AN:

3470

East Asian (EAS)

AF:

0.0788

AC:

408

AN:

5178

South Asian (SAS)

AF:

0.0133

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0673

AC:

714

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0186

AC:

1263

AN:

68028

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

233

466

699

932

1165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0216

Hom.:

168

Bravo

AF:

0.0273

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.0386

AC:

170

ESP6500EA

AF:

0.0153

AC:

132

ExAC

AF:

0.0265

AC:

3213

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

EpiCase

AF:

0.0174

EpiControl

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 15, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of aromatic-L-amino-acid decarboxylase

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.037

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

.;T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

N;.;.;N;N

PhyloP100

3.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.0

N;.;N;N;N

REVEL

Benign

0.098

Sift

Benign

0.066

T;.;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.0020

B;.;.;B;.

Vest4

0.064

MPC

0.29

ClinPred

0.013

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.81

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over