12-13865843-G-C

Variant names:

• chr12-13865843-G-C
• rs7301328
• NM_000834.5:c.366C>G

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.366C>G​(p.Pro122Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,612,878 control chromosomes in the GnomAD database, including 136,826 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. P122P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.42 (13790 hom., cov: 31)
  • Exomes 𝑓: 0.41 (123036 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.94
• Publications: 89 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=-0.51).
• BP6: Variant 12-13865843-G-C is Benign according to our data. Variant chr12-13865843-G-C is described in ClinVar as Benign. ClinVar VariationId is 129205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.483 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.366C>G	p.Pro122Pro	synonymous	Exon 3 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.366C>G	p.Pro122Pro	synonymous	Exon 4 of 15	NP_001400921.1	A0A8D9PHB2
	GRIN2B	NM_001413993.1		c.366C>G	p.Pro122Pro	synonymous	Exon 3 of 4	NP_001400922.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.366C>G	p.Pro122Pro	synonymous	Exon 3 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.366C>G	p.Pro122Pro	synonymous	Exon 4 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000714048.1		n.366C>G		non_coding_transcript_exon	Exon 3 of 13	ENSP00000519339.1	A0AAQ5BH89

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63823 AN: 151732 Hom.: 13774 Cov.: 31

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.394

GnomAD2 exomes AF: 0.408 AC: 102530 AN: 251152 AF XY: 0.413

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.408 AC: 596152 AN: 1461028 Hom.: 123036 Cov.: 43 AF XY: 0.411 AC XY: 298613 AN XY: 726844

African (AFR) AF: 0.489 AC: 16356 AN: 33462

American (AMR) AF: 0.304 AC: 13610 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9913 AN: 26132

East Asian (EAS) AF: 0.470 AC: 18671 AN: 39690

South Asian (SAS) AF: 0.495 AC: 42668 AN: 86238

European-Finnish (FIN) AF: 0.407 AC: 21756 AN: 53416

Middle Eastern (MID) AF: 0.353 AC: 2030 AN: 5754

European-Non Finnish (NFE) AF: 0.402 AC: 446203 AN: 1111254

Other (OTH) AF: 0.413 AC: 24945 AN: 60358

GnomAD4 genome AF: 0.421 AC: 63881 AN: 151850 Hom.: 13790 Cov.: 31 AF XY: 0.421 AC XY: 31253 AN XY: 74234

African (AFR) AF: 0.488 AC: 20213 AN: 41402

American (AMR) AF: 0.343 AC: 5233 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1390 AN: 3466

East Asian (EAS) AF: 0.475 AC: 2454 AN: 5170

South Asian (SAS) AF: 0.496 AC: 2371 AN: 4784

European-Finnish (FIN) AF: 0.395 AC: 4173 AN: 10552

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26940 AN: 67904

Other (OTH) AF: 0.394 AC: 830 AN: 2104

Alfa AF: 0.400 Hom.: 3958

Bravo AF: 0.418

Asia WGS AF: 0.488 AC: 1697 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.389

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		2.9
Mutation Taster		=86/14	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: rs7301328; hg19: chr12-14018777; COSMIC: COSV74205708; COSMIC: COSV74205708;