rs1805522

Variant names:

• chr12-13608807-G-A
• rs1805522
• NM_000834.5:c.1806C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-13608807-G-A
• chr12-13608807-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000834.5(GRIN2B):​c.1806C>T​(p.Ile602Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,613,438 control chromosomes in the GnomAD database, including 2,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I602I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (262 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2569 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.977
• Publications: 21 publications found

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]

GRIN2B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• developmental and epileptic encephalopathy, 27

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• intellectual disability, autosomal dominant 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287928 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 12-13608807-G-A is Benign according to our data. Variant chr12-13608807-G-A is described in ClinVar as Benign. ClinVar VariationId is 129201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.977 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1806C>T	p.Ile602Ile	synonymous_variant	Exon 10 of 14	ENST00000609686.4	NP_000825.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1806C>T	p.Ile602Ile	synonymous_variant	Exon 10 of 14	1	NM_000834.5	ENSP00000477455.1

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7783 AN: 152078 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0809

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0652 AC: 16388 AN: 251350 AF XY: 0.0658

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.0788

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.0784

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0481 AC: 70319 AN: 1461242 Hom.: 2569 Cov.: 32 AF XY: 0.0500 AC XY: 36379 AN XY: 726970

African (AFR) AF: 0.0481 AC: 1611 AN: 33458

American (AMR) AF: 0.0761 AC: 3403 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 521 AN: 26132

East Asian (EAS) AF: 0.183 AC: 7262 AN: 39692

South Asian (SAS) AF: 0.115 AC: 9877 AN: 86232

European-Finnish (FIN) AF: 0.0809 AC: 4319 AN: 53416

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5768

European-Non Finnish (NFE) AF: 0.0361 AC: 40140 AN: 1111442

Other (OTH) AF: 0.0494 AC: 2983 AN: 60378

GnomAD4 genome AF: 0.0511 AC: 7780 AN: 152196 Hom.: 262 Cov.: 32 AF XY: 0.0547 AC XY: 4067 AN XY: 74404

African (AFR) AF: 0.0435 AC: 1806 AN: 41540

American (AMR) AF: 0.0562 AC: 859 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3466

East Asian (EAS) AF: 0.164 AC: 848 AN: 5168

South Asian (SAS) AF: 0.131 AC: 628 AN: 4810

European-Finnish (FIN) AF: 0.0809 AC: 857 AN: 10594

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0383 AC: 2603 AN: 68018

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0356 Hom.: 171

Bravo AF: 0.0476

Asia WGS AF: 0.126 AC: 439 AN: 3478

EpiCase AF: 0.0375

EpiControl AF: 0.0324

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 06, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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. -

Jul 31, 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 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 19. Only high quality variants are reported. -

Inborn genetic diseases Benign:1

Mar 18, 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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.8
DANN	Benign	0.76
PhyloP100		0.98
PromoterAI		-0.021	Neutral
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805522; hg19: chr12-13761741; COSMIC: COSV74205189; COSMIC: COSV74205189;