17-74846088-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000835.6(GRIN2C):c.2328G>A(p.Ala776=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,144 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (16 hom.)
• Consequence: GRIN2C NM_000835.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.58

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-74846088-C-T is Benign according to our data. Variant chr17-74846088-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2648236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2C	NM_000835.6	c.2328G>A	p.Ala776=	synonymous_variant	11/13	ENST00000293190.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2C	ENST00000293190.10	c.2328G>A	p.Ala776=	synonymous_variant	11/13	1	NM_000835.6	P1
GRIN2C	ENST00000347612.4	c.2328G>A	p.Ala776=	synonymous_variant	11/12	1
GRIN2C	ENST00000584176.1	n.6071G>A		non_coding_transcript_exon_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152240 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00265 AC: 666 AN: 251266 Hom.: 2 AF XY: 0.00253 AC XY: 343 AN XY: 135806

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00388 AC: 5667 AN: 1461786 Hom.: 16 Cov.: 32 AF XY: 0.00385 AC XY: 2800 AN XY: 727206

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.00453

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152358 Hom.: 2 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74502

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00414

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

GRIN2C: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.7
Dann	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs80107421; hg19: chr17-72842227; COSMIC: COSV53117608;