17-74842569-T-TGCCCCTGTGCCCCAGAGGCCC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM4 BP6_Moderate

The NM_000835.6(GRIN2C):c.3567_3568insGGGCCTCTGGGGCACAGGGGC(p.Gly1183_Gly1189dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 772,044 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: GRIN2C NM_000835.6 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.287

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000835.6.
• BP6: Variant 17-74842569-T-TGCCCCTGTGCCCCAGAGGCCC is Benign according to our data. Variant chr17-74842569-T-TGCCCCTGTGCCCCAGAGGCCC is described in ClinVar as [Likely_benign]. Clinvar id is 3047243.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2C	NM_000835.6	c.3567_3568insGGGCCTCTGGGGCACAGGGGC	p.Gly1183_Gly1189dup	inframe_insertion	13/13	ENST00000293190.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2C	ENST00000293190.10	c.3567_3568insGGGCCTCTGGGGCACAGGGGC	p.Gly1183_Gly1189dup	inframe_insertion	13/13	1	NM_000835.6	P1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 155 AN: 150088 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.000146 AC: 34 AN: 233334 Hom.: 0 AF XY: 0.000117 AC XY: 15 AN XY: 127866

Gnomad AFR exome AF: 0.00230

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000492

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 71 AN: 621838 Hom.: 1 Cov.: 0 AF XY: 0.0000886 AC XY: 30 AN XY: 338636

Gnomad4 AFR exome AF: 0.00346

Gnomad4 AMR exome AF: 0.0000465

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.00103 AC: 155 AN: 150206 Hom.: 0 Cov.: 34 AF XY: 0.00110 AC XY: 81 AN XY: 73480

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000927 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRIN2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2022

This variant is classified as likely 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: rs768223291; hg19: chr17-72838708;