Genetic Variant GRIN2C:p.Arg1209Ser (chr17-74842510-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000835.6(GRIN2C):c.3627G>C(p.Arg1209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000319 in 626,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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: 0.0000032 ( 0 hom. )

Consequence

GRIN2C
NM_000835.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.685

Publications

0 publications found

Variant links:

Genes affected

GRIN2C (HGNC:4587): (glutamate ionotropic receptor NMDA type subunit 2C) This gene encodes a subunit of the N-methyl-D-aspartate (NMDA) receptor, which is a subtype of ionotropic glutamate receptor. NMDA receptors are found in the central nervous system, are permeable to cations and have an important role in physiological processes such as learning, memory, and synaptic development. The receptor is a tetramer of different subunits (typically heterodimer of subunit 1 with one or more of subunits 2A-D), forming a channel that is permeable to calcium, potassium, and sodium, and whose properties are determined by subunit composition. Alterations in the subunit composition of the receptor are associated with pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, depression, and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

GRIN2C Gene-Disease associations (from GenCC):

Alzheimer disease
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

GRIN2C links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056804866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2C	NM_000835.6 link	c.3627G>C	p.Arg1209Ser	missense_variant	Exon 13 of 13	ENST00000293190.10	NP_000826.2	Q14957A0A8D9PH81O15398

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2C	ENST00000293190.10 link	c.3627G>C	p.Arg1209Ser	missense_variant	Exon 13 of 13	1	NM_000835.6	ENSP00000293190.5		Q14957

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000319

AC:

AN:

626350

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

341202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17656

American (AMR)

AF:

0.00

AC:

AN:

43590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20960

East Asian (EAS)

AF:

0.00

AC:

AN:

36006

South Asian (SAS)

AF:

0.00

AC:

AN:

69610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4144

European-Non Finnish (NFE)

AF:

0.00000286

AC:

AN:

349414

Other (OTH)

AF:

0.0000303

AC:

AN:

33012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.42

M_CAP

Benign

0.0056

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.97

PhyloP100

0.69

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.58

REVEL

Benign

0.023

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.041

Polyphen

0.0010

Vest4

0.054

MutPred

0.29

Gain of phosphorylation at R1209 (P = 0.0503);

MVP

0.35

MPC

0.56

ClinPred

0.089

GERP RS

-1.4

Varity_R

0.17

gMVP

0.39

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over