Variant 17-74843512-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000835.6(GRIN2C):c.2625C>G(p.Ser875Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GRIN2C
NM_000835.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity NMDE3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14395678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2C	NM_000835.6 linkuse as main transcript	c.2625C>G	p.Ser875Arg	missense_variant	13/13	ENST00000293190.10	NP_000826.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2C	ENST00000293190.10 linkuse as main transcript	c.2625C>G	p.Ser875Arg	missense_variant	13/13	1	NM_000835.6	ENSP00000293190	P1
GRIN2C	ENST00000584176.1 linkuse as main transcript	n.6368C>G		non_coding_transcript_exon_variant	9/9	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000776

AC:

AN:

128944

Hom.:

AF XY:

0.00

AC XY:

AN XY:

70464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000958

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.24e-7

AC:

AN:

1381164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

681590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.2625C>G (p.S875R) alteration is located in exon 13 (coding exon 12) of the GRIN2C gene. This alteration results from a C to G substitution at nucleotide position 2625, causing the serine (S) at amino acid position 875 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

Benign

0.30

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

M_CAP

Benign

0.0099

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.78

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.71

REVEL

Benign

0.034

Sift

Benign

0.30

Sift4G

Benign

0.58

Polyphen

0.052

Vest4

0.15

MutPred

0.18

Loss of phosphorylation at S875 (P = 0.0268);

MVP

0.52

MPC

0.79

ClinPred

0.18

GERP RS

3.8

Varity_R

0.11

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over