17-74842556-AGCCCCAGAGTCCTGCCCCTGT-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BS1 BS2

The NM_000835.6(GRIN2C):c.3560_3580del(p.His1187_Gly1193del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 777,666 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (16 hom., cov: 34)
  • Exomes 𝑓: 0.00095 (5 hom.)
• Consequence: GRIN2C NM_000835.6 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.82

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000835.6.
• BP6: Variant 17-74842556-AGCCCCAGAGTCCTGCCCCTGT-A is Benign according to our data. Variant chr17-74842556-AGCCCCAGAGTCCTGCCCCTGT-A is described in ClinVar as [Benign]. Clinvar id is 3052629.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00698 (1061/152092) while in subpopulation AFR AF= 0.0241 (996/41388). AF 95% confidence interval is 0.0228. There are 16 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2C	NM_000835.6	c.3560_3580del	p.His1187_Gly1193del	inframe_deletion	13/13	ENST00000293190.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2C	ENST00000293190.10	c.3560_3580del	p.His1187_Gly1193del	inframe_deletion	13/13	1	NM_000835.6	P1

Frequencies

GnomAD3 genomes AF: 0.00698 AC: 1061 AN: 151974 Hom.: 16 Cov.: 34

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00155 AC: 372 AN: 240596 Hom.: 4 AF XY: 0.00128 AC XY: 168 AN XY: 131522

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000233

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000948 AC: 593 AN: 625574 Hom.: 5 AF XY: 0.000816 AC XY: 278 AN XY: 340740

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000744

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00698 AC: 1061 AN: 152092 Hom.: 16 Cov.: 34 AF XY: 0.00679 AC XY: 505 AN XY: 74370

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00347 Hom.: 0

Bravo AF: 0.00822

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRIN2C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs577805282; hg19: chr17-72838695;