Genetic Variant DDC:p.Pro210Arg (chr7-50528222-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001082971.2(DDC):c.629C>G(p.Pro210Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P210L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

DDC
NM_001082971.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.36

Publications

16 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

DDC links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082971.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDC	NM_001082971.2	MANE Select	c.629C>G	p.Pro210Arg	missense	Exon 6 of 15	NP_001076440.2	A0A0S2Z3N4
DDC	NM_000790.4		c.629C>G	p.Pro210Arg	missense	Exon 6 of 15	NP_000781.2	P20711-1
DDC	NM_001242886.2		c.515C>G	p.Pro172Arg	missense	Exon 5 of 14	NP_001229815.2	A0A087WV24

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDC	ENST00000444124.7	TSL:1 MANE Select	c.629C>G	p.Pro210Arg	missense	Exon 6 of 15	ENSP00000403644.2	P20711-1
DDC	ENST00000357936.9	TSL:1	c.629C>G	p.Pro210Arg	missense	Exon 6 of 15	ENSP00000350616.5	P20711-1
DDC	ENST00000380984.4	TSL:1	c.629C>G	p.Pro210Arg	missense	Exon 6 of 10	ENSP00000370371.4	P20711-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.9

PhyloP100

9.4

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.27

Sift

Benign

0.042

Sift4G

Benign

0.069

Polyphen

0.067

Vest4

0.59

MutPred

0.47

Gain of MoRF binding (P = 4e-04)

MVP

0.80

MPC

0.89

ClinPred

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.86

Mutation Taster

=38/62

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over