NM_000834.5:c.3534C>T

Variant names:

• chr12-13563704-G-A
• rs1806191
• NM_000834.5:c.3534C>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.3534C>T​(p.His1178His) 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:11
• Conservation: PhyloP100: 1.13
• Publications: 34 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=-0.54).
• BP6: Variant 12-13563704-G-A is Benign according to our data. Variant chr12-13563704-G-A is described in ClinVar as Benign. ClinVar VariationId is 129204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.3534C>T	p.His1178His	synonymous	Exon 14 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.3534C>T	p.His1178His	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.3534C>T	p.His1178His	synonymous	Exon 14 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.3534C>T	p.His1178His	synonymous	Exon 15 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000637214.1	TSL:5	c.69+44899C>T		intron	N/A	ENSP00000489997.1	A0A1B0GU78

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

GnomAD2 exomes AF: 0.399 AC: 99507 AN: 249604 AF XY: 0.398

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 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

African (AFR) AF: 0.192 AC: 6418 AN: 33478

American (AMR) AF: 0.459 AC: 20504 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11707 AN: 26136

East Asian (EAS) AF: 0.0125 AC: 495 AN: 39700

South Asian (SAS) AF: 0.246 AC: 21184 AN: 86258

European-Finnish (FIN) AF: 0.413 AC: 21791 AN: 52778

Middle Eastern (MID) AF: 0.447 AC: 2578 AN: 5768

European-Non Finnish (NFE) AF: 0.517 AC: 575008 AN: 1111940

Other (OTH) AF: 0.431 AC: 26030 AN: 60378

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

African (AFR) AF: 0.201 AC: 8338 AN: 41494

American (AMR) AF: 0.449 AC: 6860 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1577 AN: 3470

East Asian (EAS) AF: 0.0143 AC: 74 AN: 5168

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4816

European-Finnish (FIN) AF: 0.417 AC: 4413 AN: 10574

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34546 AN: 67922

Other (OTH) AF: 0.401 AC: 843 AN: 2104

Alfa AF: 0.465 Hom.: 68627

Bravo AF: 0.380

Asia WGS AF: 0.139 AC: 488 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 (3)
-	-	1	Developmental and epileptic encephalopathy, 27 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 6 (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	-0.54
CADD	Benign	3.6
DANN	Benign	0.53
PhyloP100		1.1
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: rs1806191; hg19: chr12-13716638; COSMIC: COSV74204642; COSMIC: COSV74204642;