11-113412617-G-T

Position:

• chr11-113412617-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000795.4(DRD2):​c.1077C>A​(p.Ser359Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DRD2 NM_000795.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.86

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27005422).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRD2	NM_000795.4	c.1077C>A	p.Ser359Arg	missense_variant	7/8	ENST00000362072.8	NP_000786.1
DRD2	NM_016574.4	c.990C>A	p.Ser330Arg	missense_variant	6/7		NP_057658.2
DRD2	XM_017017296.3	c.1077C>A	p.Ser359Arg	missense_variant	7/8		XP_016872785.1
DRD2	XM_047426511.1	c.990C>A	p.Ser330Arg	missense_variant	6/7		XP_047282467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRD2	ENST00000362072.8	c.1077C>A	p.Ser359Arg	missense_variant	7/8	1	NM_000795.4	ENSP00000354859.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.1077C>A (p.S359R) alteration is located in exon 7 (coding exon 6) of the DRD2 gene. This alteration results from a C to A substitution at nucleotide position 1077, causing the serine (S) at amino acid position 359 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;.;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.4	.;L;.;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.55	P;B;P;B;.
Vest4		0.41
MutPred		0.40		.;Loss of phosphorylation at S359 (P = 0.0059);.;Loss of phosphorylation at S359 (P = 0.0059);.;
MVP		0.65
MPC		0.97
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.54
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs777971489; hg19: chr11-113283339;