17-74843279-G-T

Variant names:

• chr17-74843279-G-T
• rs1161057621
• NM_000835.6:c.2858C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000835.6(GRIN2C):​c.2858C>A​(p.Pro953Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 871,170 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P953R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: GRIN2C NM_000835.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.365
• Publications: 0 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: 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=0.07641858).

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.2858C>A	p.Pro953Gln	missense	Exon 13 of 13	NP_000826.2	Q14957
	GRIN2C	NR_103735.2		n.3011C>A		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2C	ENST00000293190.10	TSL:1 MANE Select	c.2858C>A	p.Pro953Gln	missense	Exon 13 of 13	ENSP00000293190.5	Q14957
	GRIN2C	ENST00000940919.1		c.2921C>A	p.Pro974Gln	missense	Exon 14 of 14	ENSP00000610978.1
	GRIN2C	ENST00000940918.1		c.2882C>A	p.Pro961Gln	missense	Exon 13 of 13	ENSP00000610977.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 21852 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000115 AC: 1 AN: 871170 Hom.: 0 Cov.: 11 AF XY: 0.00000231 AC XY: 1 AN XY: 433808

African (AFR) AF: 0.00 AC: 0 AN: 17326

American (AMR) AF: 0.00 AC: 0 AN: 14842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15872

East Asian (EAS) AF: 0.00 AC: 0 AN: 26590

South Asian (SAS) AF: 0.00 AC: 0 AN: 51870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2830

European-Non Finnish (NFE) AF: 0.00000149 AC: 1 AN: 672604

Other (OTH) AF: 0.00 AC: 0 AN: 39284

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.9
DANN	Benign	0.80
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.36
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.013
Sift	Benign	0.45	T
Sift4G	Benign	0.53	T
Polyphen		0.022	B
Vest4		0.20
MutPred		0.27		Loss of glycosylation at P953 (P = 0.0053)
MVP		0.34
MPC		0.48
ClinPred		0.041	T
GERP RS		1.1
Varity_R		0.033
gMVP		0.14

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: rs1161057621; hg19: chr17-72839418;