17-74842510-C-A

Variant names:

• chr17-74842510-C-A
• rs3744215
• NM_000835.6:c.3627G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000835.6(GRIN2C):​c.3627G>T​(p.Arg1209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 778,338 control chromosomes in the GnomAD database, including 32,472 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.28 (6313 hom., cov: 33)
  • Exomes 𝑓: 0.28 (26159 hom.)
• Consequence: GRIN2C NM_000835.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.685
• Publications: 38 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014544725).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2C	NM_000835.6	c.3627G>T	p.Arg1209Ser	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.3627G>T	p.Arg1209Ser	missense_variant	Exon 13 of 13	1	NM_000835.6	ENSP00000293190.5

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42966 AN: 151956 Hom.: 6302 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.288

GnomAD2 exomes AF: 0.280 AC: 68824 AN: 245404 AF XY: 0.283

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.282 AC: 176421 AN: 626264 Hom.: 26159 Cov.: 0 AF XY: 0.282 AC XY: 96292 AN XY: 341146

African (AFR) AF: 0.298 AC: 5264 AN: 17644

American (AMR) AF: 0.174 AC: 7575 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 8011 AN: 20958

East Asian (EAS) AF: 0.431 AC: 15506 AN: 36004

South Asian (SAS) AF: 0.276 AC: 19218 AN: 69606

European-Finnish (FIN) AF: 0.286 AC: 14867 AN: 51952

Middle Eastern (MID) AF: 0.312 AC: 1294 AN: 4144

European-Non Finnish (NFE) AF: 0.273 AC: 95254 AN: 349368

Other (OTH) AF: 0.286 AC: 9432 AN: 33010

GnomAD4 genome AF: 0.283 AC: 43004 AN: 152074 Hom.: 6313 Cov.: 33 AF XY: 0.280 AC XY: 20816 AN XY: 74312

African (AFR) AF: 0.301 AC: 12484 AN: 41496

American (AMR) AF: 0.218 AC: 3334 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1337 AN: 3470

East Asian (EAS) AF: 0.411 AC: 2109 AN: 5136

South Asian (SAS) AF: 0.273 AC: 1317 AN: 4816

European-Finnish (FIN) AF: 0.286 AC: 3028 AN: 10592

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18496 AN: 67956

Other (OTH) AF: 0.288 AC: 609 AN: 2114

Alfa AF: 0.276 Hom.: 13216

Bravo AF: 0.282

TwinsUK AF: 0.271 AC: 1005

ALSPAC AF: 0.286 AC: 1103

ESP6500AA AF: 0.308 AC: 1356

ESP6500EA AF: 0.283 AC: 2433

ExAC AF: 0.279 AC: 33837

Asia WGS AF: 0.309 AC: 1075 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.69
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.023
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.041	D
Polyphen		0.0010	B
Vest4		0.054
MutPred		0.29		Gain of phosphorylation at R1209 (P = 0.0503);
MPC		0.56
ClinPred		0.0087	T
GERP RS		-1.4
Varity_R		0.17
gMVP		0.39
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3744215; hg19: chr17-72838649; COSMIC: COSV53110825; COSMIC: COSV53110825;