Genetic Variant GRIN2C:p.Val971Leu (chr17-74843226-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000835.6(GRIN2C):c.2911G>T(p.Val971Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 439,308 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

GRIN2C
NM_000835.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.341

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06960955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000835.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2C	NM_000835.6	MANE Select	c.2911G>T	p.Val971Leu	missense	Exon 13 of 13	NP_000826.2	Q14957
	GRIN2C	NR_103735.2		n.3064G>T		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2C	ENST00000293190.10	TSL:1 MANE Select	c.2911G>T	p.Val971Leu	missense	Exon 13 of 13	ENSP00000293190.5	Q14957
GRIN2C	ENST00000940919.1		c.2974G>T	p.Val992Leu	missense	Exon 14 of 14	ENSP00000610978.1
GRIN2C	ENST00000940918.1		c.2935G>T	p.Val979Leu	missense	Exon 13 of 13	ENSP00000610977.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000228

AC:

AN:

439308

Hom.:

Cov.:

AF XY:

0.00000448

AC XY:

AN XY:

223298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9314

American (AMR)

AF:

0.00

AC:

AN:

7466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11036

East Asian (EAS)

AF:

0.00

AC:

AN:

22918

South Asian (SAS)

AF:

0.0000434

AC:

AN:

23026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1780

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

313642

Other (OTH)

AF:

0.00

AC:

AN:

23790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.6

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.13

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.45

M_CAP

Benign

0.030

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

PhyloP100

0.34

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.63

REVEL

Benign

0.036

Sift

Benign

0.10

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.019

MutPred

0.23

Gain of helix (P = 0.0128)

MVP

0.16

MPC

0.47

ClinPred

0.11

GERP RS

2.4

Varity_R

0.079

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over