rs45600931

Variant names:

• chr12-13563740-G-A
• rs45600931
• NM_000834.5:c.3498C>T
• GRIN2B p.Ser1166Ser

Your query was ambiguous. Multiple possible variants found:

• chr12-13563740-G-A
• chr12-13563740-G-C
• chr12-13563740-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000834.5(GRIN2B):​c.3498C>T​(p.Ser1166Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00724 in 1,613,862 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (57 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.55
• Publications: 5 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: Labcorp Genetics (formerly Invitae), G2P
• intellectual disability, autosomal dominant 6

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-13563740-G-A is Benign according to our data. Variant chr12-13563740-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00519 (791/152268) while in subpopulation NFE AF = 0.00779 (530/68018). AF 95% confidence interval is 0.00724. There are 3 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 791 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	NM_000834.5	MANE Select	c.3498C>T	p.Ser1166Ser	synonymous	Exon 14 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.3498C>T	p.Ser1166Ser	synonymous	Exon 15 of 15	NP_001400921.1	A0A8D9PHB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.3498C>T	p.Ser1166Ser	synonymous	Exon 14 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.3498C>T	p.Ser1166Ser	synonymous	Exon 15 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000637214.1	TSL:5	c.69+44863C>T		intron	N/A	ENSP00000489997.1	A0A1B0GU78

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 790 AN: 152150 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00778

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00602 AC: 1509 AN: 250582 AF XY: 0.00603

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00851

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00745 AC: 10891 AN: 1461594 Hom.: 57 Cov.: 37 AF XY: 0.00737 AC XY: 5356 AN XY: 727100

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00429 AC: 370 AN: 86258

European-Finnish (FIN) AF: 0.0144 AC: 765 AN: 53134

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00831 AC: 9246 AN: 1112004

Other (OTH) AF: 0.00618 AC: 373 AN: 60392

GnomAD4 genome AF: 0.00519 AC: 791 AN: 152268 Hom.: 3 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74456

African (AFR) AF: 0.00128 AC: 53 AN: 41548

American (AMR) AF: 0.00418 AC: 64 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00779 AC: 530 AN: 68018

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00532 Hom.: 2

Bravo AF: 0.00467

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Intellectual disability, autosomal dominant 6 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.76
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45600931;

hg19: chr12-13716674;