rs2227840

Positions:

• chr4-9782214-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000798.5(DRD5):​c.185G>C​(p.Cys62Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DRD5 NM_000798.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.43

Genes affected

DRD5 (HGNC:3026): (dopamine receptor D5) This gene encodes the D5 subtype of the dopamine receptor. The D5 subtype is a G-protein coupled receptor which stimulates adenylyl cyclase. This receptor is expressed in neurons in the limbic regions of the brain. It has a 10-fold higher affinity for dopamine than the D1 subtype. Pseudogenes related to this gene reside on chromosomes 1 and 2. [provided by RefSeq, Jul 2008]

SLC2A9 (HGNC:13446): (solute carrier family 2 member 9) This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRD5	NM_000798.5	c.185G>C	p.Cys62Ser	missense_variant	1/1	ENST00000304374.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRD5	ENST00000304374.4	c.185G>C	p.Cys62Ser	missense_variant	1/1		NM_000798.5	P1
SLC2A9	ENST00000503803.5	n.386-2149C>G		intron_variant, non_coding_transcript_variant		3
SLC2A9	ENST00000508585.5	n.182-10845C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ExAC AF: 0.000124 AC: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.034	D
Polyphen		0.89	P
Vest4		0.87
MutPred		0.25		Gain of glycosylation at C62 (P = 0.0427);
MVP		0.60
MPC		0.80
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2227840; hg19: chr4-9783838;