NM_000834.5:c.4197T>C

Variant names:

• chr12-13563041-A-G
• rs1805247
• NM_000834.5:c.4197T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000834.5(GRIN2B):​c.4197T>C​(p.His1399His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,904 control chromosomes in the GnomAD database, including 12,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3007 hom., cov: 33)
  • Exomes 𝑓: 0.10 (9505 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.0850

Genes affected

GRIN2B (HGNC:4586): (glutamate ionotropic receptor NMDA type subunit 2B) This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-13563041-A-G is Benign according to our data. Variant chr12-13563041-A-G is described in ClinVar as [Benign]. Clinvar id is 98432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13563041-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.085 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.4197T>C	p.His1399His	synonymous_variant	Exon 14 of 14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.4197T>C	p.His1399His	synonymous_variant	Exon 15 of 15		NP_001400921.1
GRIN2B	XM_005253351.3	c.1983T>C	p.His661His	synonymous_variant	Exon 4 of 4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.4197T>C	p.His1399His	synonymous_variant	Exon 14 of 14	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000637214.1	c.69+45562T>C		intron_variant	Intron 1 of 1	5		ENSP00000489997.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25199 AN: 152054 Hom.: 2982 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0845

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.130 AC: 32584 AN: 251330 Hom.: 2779 AF XY: 0.129 AC XY: 17501 AN XY: 135866

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.0872

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0868

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0999 AC: 146040 AN: 1461732 Hom.: 9505 Cov.: 34 AF XY: 0.103 AC XY: 74824 AN XY: 727142

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0867

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.166 AC: 25263 AN: 152172 Hom.: 3007 Cov.: 33 AF XY: 0.166 AC XY: 12353 AN XY: 74418

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0845

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0845

Gnomad4 OTH AF: 0.152

Alfa AF: 0.104 Hom.: 1584

Bravo AF: 0.173

Asia WGS AF: 0.199 AC: 693 AN: 3478

EpiCase AF: 0.0846

EpiControl AF: 0.0799

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Psychiatry Genetics Yale University

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 6 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 27 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.2
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805247; hg19: chr12-13715975; COSMIC: COSV74205188; COSMIC: COSV74205188;