rs6263

Variant names:

• chr7-50528202-T-C
• rs6263
• NM_001082971.2:c.649A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.03
• Publications: 15 publications found

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

ACMG classification

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDC	NM_001082971.2	MANE Select	c.649A>G	p.Met217Val	missense	Exon 6 of 15	NP_001076440.2	A0A0S2Z3N4
	DDC	NM_000790.4		c.649A>G	p.Met217Val	missense	Exon 6 of 15	NP_000781.2	P20711-1
	DDC	NM_001242886.2		c.535A>G	p.Met179Val	missense	Exon 5 of 14	NP_001229815.2	A0A087WV24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDC	ENST00000444124.7	TSL:1 MANE Select	c.649A>G	p.Met217Val	missense	Exon 6 of 15	ENSP00000403644.2	P20711-1
	DDC	ENST00000357936.9	TSL:1	c.649A>G	p.Met217Val	missense	Exon 6 of 15	ENSP00000350616.5	P20711-1
	DDC	ENST00000380984.4	TSL:1	c.649A>G	p.Met217Val	missense	Exon 6 of 10	ENSP00000370371.4	P20711-2

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4535 AN: 152192 Hom.: 99 Cov.: 32

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

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.: 31 AF XY: 0.0213 AC XY: 15486 AN XY: 727188

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: 50 AN: 5680

European-Non Finnish (NFE) AF: 0.0182 AC: 20203 AN: 1111998

Other (OTH) AF: 0.0229 AC: 1382 AN: 60380

GnomAD4 genome AF: 0.0298 AC: 4545 AN: 152310 Hom.: 100 Cov.: 32 AF XY: 0.0315 AC XY: 2344 AN XY: 74474

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: 64 AN: 4830

European-Finnish (FIN) AF: 0.0673 AC: 714 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1263 AN: 68028

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0216 Hom.: 168

Bravo AF: 0.0273

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0187 AC: 72

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Deficiency of aromatic-L-amino-acid decarboxylase (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		3.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.098
Sift	Benign	0.066	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.064
MPC		0.29
ClinPred		0.013	T
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)

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: rs6263; hg19: chr7-50595900; COSMIC: COSV107442195; COSMIC: COSV107442195;