DRD2 p.Pro319Pro

Variant names:

• chr11-113412737-G-A
• rs6277
• NM_000795.4:c.957C>T
• DRD2 p.Pro319Pro

Your query was ambiguous. Multiple possible variants found:

• chr11-113412737-G-A
• chr11-113412737-G-C
• chr11-113412737-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_000795.4(DRD2):c.957C>T (p.Pro319Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.488 (AC=787,261) in the gnomAD database across 1,613,936 control chromosomes, including 206,505 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.546. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13521 hom., cov: 32)
  • Exomes 𝑓: 0.50 (192984 hom.)
• Consequence: DRD2 NM_000795.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.127
• Publications: 526 publications found

Genes affected

DRD2 (HGNC:3023): (dopamine receptor D2) This gene encodes the D2 subtype of the dopamine receptor. This G-protein coupled receptor inhibits adenylyl cyclase activity. A missense mutation in this gene causes myoclonus dystonia; other mutations have been associated with schizophrenia. Alternative splicing of this gene results in two transcript variants encoding different isoforms. A third variant has been described, but it has not been determined whether this form is normal or due to aberrant splicing. [provided by RefSeq, Jul 2008]

DRD2 Gene-Disease associations (from GenCC):

• combined dystonia

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -17 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BP7: Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5461 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000795.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD2	NM_000795.4	MANE Select	c.957C>T	p.Pro319Pro	synonymous	Exon 7 of 8	NP_000786.1	P14416-1
	DRD2	NM_001440368.1		c.954C>T	p.Pro318Pro	synonymous	Exon 7 of 8	NP_001427297.1	F8VUV1
	DRD2	NM_016574.4		c.870C>T	p.Pro290Pro	synonymous	Exon 6 of 7	NP_057658.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD2	ENST00000362072.8	TSL:1 MANE Select	c.957C>T	p.Pro319Pro	synonymous	Exon 7 of 8	ENSP00000354859.3	P14416-1
	DRD2	ENST00000542968.5	TSL:1	c.957C>T	p.Pro319Pro	synonymous	Exon 6 of 7	ENSP00000442172.1	P14416-1
	DRD2	ENST00000544518.5	TSL:1	c.954C>T	p.Pro318Pro	synonymous	Exon 6 of 7	ENSP00000441068.1	F8VUV1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	0.376	57167	13534	151962	32
GnomAD2 exomes	0.411	103247		251142
GnomAD4 exome	0.499	730118	192984	1461856	93
GnomAD4 genome	0.376	57143	13521	152080	32
TOPMed (Bravo)	0.358
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.469	153289	39784	326542
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.438	1025	250	2342
ChinaMAP Phase 1	0.0578
Denmark Genome	0.530	159		300
ESP6500 (Exome Variant Server)	0.409	5313		12994
GenomeAsia100K	0.193	674		3478
Korea4K (4,157 Koreans)	0.0610	443		7234
Qatari Genome	0.362	727		2010
ToMMo 61KJPN (+60KJPN MNV)	0.0580	7121	225	122674
Turkish Variome	0.548	3679	1031	6712
UK10K	0.552	4176		7562
WBBC (Westlake BioBank for Chinese) pilot	0.0609	546	13	8960

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.545 *	5243	9616	0.553 *	5766	10420
BipEx(Bipolar disorder (including schizoaffective))	0.539	15325	28420	0.542	15625	28844
Epi25(Epilepsy)	0.462	19367	41958	0.467	31245	66888
SCHEMA(Schizophrenia)	0.341	47165	138354	0.380	89745	235966

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Dystonic disorder (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	0.017
BayesDel_noAF	Benign	-	-0.78
CADD	Benign	-	0.79
DANN	Benign	-	0.75
GPN-Star LLR	N/A	-	3.0
GPN-Star score	N/A	-	2.7
Mutation Taster	N/A	polymorphism (auto)	93/7
PhyloP100	Benign	-	-0.13

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.010
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.010

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6277;

hg19: chr11-113283459;

COSMIC: COSV60757274;

COSMIC: COSV60757274;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar