rs1806191

chr12-13563704-G-Achr12-13563704-G-T

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.3534C>T(p.His1178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,613,184 control chromosomes in the GnomAD database, including 184,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12927 hom., cov: 32)
  • Exomes 𝑓: 0.47 (171123 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.13

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=-0.54).
• BP6: Variant 12-13563704-G-A is Benign according to our data. Variant chr12-13563704-G-A is described in ClinVar as [Benign]. Clinvar id is 129204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13563704-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.3534C>T	p.His1178=	synonymous_variant	14/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.3534C>T	p.His1178=	synonymous_variant	15/15
GRIN2B	XM_005253351.3	c.1320C>T	p.His440=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.3534C>T	p.His1178=	synonymous_variant	14/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+44899C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58380 AN: 151912 Hom.: 12922 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.402

GnomAD3 exomes AF: 0.399 AC: 99507 AN: 249604 Hom.: 22909 AF XY: 0.398 AC XY: 53761 AN XY: 134980

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.0139

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.431

GnomAD4 exome AF: 0.469 AC: 685715 AN: 1461154 Hom.: 171123 Cov.: 56 AF XY: 0.463 AC XY: 336620 AN XY: 726932

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.459

Gnomad4 ASJ exome AF: 0.448

Gnomad4 EAS exome AF: 0.0125

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.431

GnomAD4 genome AF: 0.384 AC: 58396 AN: 152030 Hom.: 12927 Cov.: 32 AF XY: 0.377 AC XY: 27991 AN XY: 74314

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.401

Alfa AF: 0.474 Hom.: 36264

Bravo AF: 0.380

Asia WGS AF: 0.139 AC: 488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Intellectual disability, autosomal dominant 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Developmental and epileptic encephalopathy, 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	3.6
Dann	Benign	0.53

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: rs1806191; hg19: chr12-13716638; COSMIC: COSV74204642; COSMIC: COSV74204642;