chr17-74843247-C-G

Variant names:

• chr17-74843247-C-G
• NM_000835.6:c.2890G>C

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.2890G>C​(p.Asp964His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000177 in 564,570 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: GRIN2C NM_000835.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• 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=0.07958406).

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.2890G>C	p.Asp964His	missense	Exon 13 of 13	NP_000826.2	Q14957
	GRIN2C	NR_103735.2		n.3043G>C		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.2890G>C	p.Asp964His	missense	Exon 13 of 13	ENSP00000293190.5	Q14957
	GRIN2C	ENST00000940919.1		c.2953G>C	p.Asp985His	missense	Exon 14 of 14	ENSP00000610978.1
	GRIN2C	ENST00000940918.1		c.2914G>C	p.Asp972His	missense	Exon 13 of 13	ENSP00000610977.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000177 AC: 1 AN: 564570 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 283470

African (AFR) AF: 0.00 AC: 0 AN: 11540

American (AMR) AF: 0.00 AC: 0 AN: 7660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12088

East Asian (EAS) AF: 0.00 AC: 0 AN: 23684

South Asian (SAS) AF: 0.00 AC: 0 AN: 29900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2050

European-Non Finnish (NFE) AF: 0.00000236 AC: 1 AN: 422968

Other (OTH) AF: 0.00 AC: 0 AN: 28118

GnomAD4 genome Cov.: 32

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	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.7
DANN	Benign	0.73
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.028
Sift	Uncertain	0.010	D
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.066
MutPred		0.16		Gain of methylation at R967 (P = 0.0474)
MVP		0.34
MPC		0.64
ClinPred		0.14	T
GERP RS		-0.20
Varity_R		0.10
gMVP		0.32

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

hg19: chr17-72839386;