12-13564574-G-A

Variant names:

• chr12-13564574-G-A
• rs1806201
• NM_000834.5:c.2664C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000834.5(GRIN2B):​c.2664C>T​(p.Thr888Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,394 control chromosomes in the GnomAD database, including 69,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5287 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64019 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.59
• Publications: 104 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: 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=-0.79).
• BP6: Variant 12-13564574-G-A is Benign according to our data. Variant chr12-13564574-G-A is described in ClinVar as Benign. ClinVar VariationId is 98437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

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.2664C>T	p.Thr888Thr	synonymous	Exon 14 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.2664C>T	p.Thr888Thr	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.2664C>T	p.Thr888Thr	synonymous	Exon 14 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.2664C>T	p.Thr888Thr	synonymous	Exon 15 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000637214.1	TSL:5	c.69+44029C>T		intron	N/A	ENSP00000489997.1	A0A1B0GU78

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37346 AN: 151914 Hom.: 5282 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.316 AC: 79410 AN: 251050 AF XY: 0.320

Gnomad AFR exome AF: 0.0991

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.523

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.289 AC: 421632 AN: 1461362 Hom.: 64019 Cov.: 39 AF XY: 0.292 AC XY: 212222 AN XY: 727022

African (AFR) AF: 0.0967 AC: 3238 AN: 33476

American (AMR) AF: 0.323 AC: 14449 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8764 AN: 26132

East Asian (EAS) AF: 0.495 AC: 19652 AN: 39696

South Asian (SAS) AF: 0.409 AC: 35253 AN: 86232

European-Finnish (FIN) AF: 0.365 AC: 19460 AN: 53350

Middle Eastern (MID) AF: 0.262 AC: 1511 AN: 5766

European-Non Finnish (NFE) AF: 0.271 AC: 301502 AN: 1111606

Other (OTH) AF: 0.295 AC: 17803 AN: 60380

GnomAD4 genome AF: 0.246 AC: 37355 AN: 152032 Hom.: 5287 Cov.: 32 AF XY: 0.256 AC XY: 19005 AN XY: 74304

African (AFR) AF: 0.104 AC: 4313 AN: 41502

American (AMR) AF: 0.286 AC: 4371 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3470

East Asian (EAS) AF: 0.509 AC: 2608 AN: 5122

South Asian (SAS) AF: 0.401 AC: 1930 AN: 4816

European-Finnish (FIN) AF: 0.367 AC: 3879 AN: 10558

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18221 AN: 67958

Other (OTH) AF: 0.265 AC: 559 AN: 2106

Alfa AF: 0.259 Hom.: 13216

Bravo AF: 0.235

Asia WGS AF: 0.432 AC: 1499 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	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	-0.79
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		-1.6
Mutation Taster		=99/1	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: rs1806201; hg19: chr12-13717508; COSMIC: COSV74206013; COSMIC: COSV74206013;