chr17-74843325-G-C

Variant names:

• chr17-74843325-G-C
• rs771659192
• NM_000835.6:c.2812C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000835.6(GRIN2C):​c.2812C>G​(p.Pro938Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000656 in 1,462,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: GRIN2C NM_000835.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0980

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08252266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2C	NM_000835.6	c.2812C>G	p.Pro938Ala	missense_variant	Exon 13 of 13	ENST00000293190.10	NP_000826.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2C	ENST00000293190.10	c.2812C>G	p.Pro938Ala	missense_variant	Exon 13 of 13	1	NM_000835.6	ENSP00000293190.5
GRIN2C	ENST00000584176.1	n.*39C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000260 AC: 3 AN: 115540 Hom.: 0 AF XY: 0.0000158 AC XY: 1 AN XY: 63338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000432

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000233

Gnomad OTH exome AF: 0.000274

GnomAD4 exome AF: 0.0000710 AC: 93 AN: 1310732 Hom.: 0 Cov.: 23 AF XY: 0.0000696 AC XY: 45 AN XY: 646470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000580

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: 0.0000871

Gnomad4 OTH exome AF: 0.0000364

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2812C>G (p.P938A) 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 2812, causing the proline (P) at amino acid position 938 to be replaced by an alanine (A). 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	0.055
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.5
DANN	Benign	0.82
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.023
Sift	Benign	0.39	T
Sift4G	Benign	0.13	T
Polyphen		0.015	B
Vest4		0.16
MutPred		0.17		Loss of glycosylation at P938 (P = 0.0387);
MVP		0.35
MPC		0.46
ClinPred		0.038	T
GERP RS		1.3
Varity_R		0.024
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

LitVar

Other links and lift over

dbSNP: rs771659192; hg19: chr17-72839464;