rs1805482

Variant names:

• chr12-13611840-G-A
• rs1805482
• NM_000834.5:c.1665C>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.1665C>T​(p.Ser555Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,612,232 control chromosomes in the GnomAD database, including 80,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5876 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74317 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0260
• Publications: 26 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

ENSG00000287928 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-13611840-G-A is Benign according to our data. Variant chr12-13611840-G-A is described in ClinVar as Benign. ClinVar VariationId is 129200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.346 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.1665C>T	p.Ser555Ser	synonymous	Exon 9 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.1665C>T	p.Ser555Ser	synonymous	Exon 10 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.1665C>T	p.Ser555Ser	synonymous	Exon 9 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.1665C>T	p.Ser555Ser	synonymous	Exon 10 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000714048.1		n.1665C>T		non_coding_transcript_exon	Exon 9 of 13	ENSP00000519339.1	A0AAQ5BH89

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39848 AN: 152026 Hom.: 5866 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.271 AC: 68162 AN: 251368 AF XY: 0.269

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.0122

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.310 AC: 452145 AN: 1460088 Hom.: 74317 Cov.: 33 AF XY: 0.305 AC XY: 221855 AN XY: 726446

African (AFR) AF: 0.155 AC: 5190 AN: 33460

American (AMR) AF: 0.389 AC: 17392 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7893 AN: 26124

East Asian (EAS) AF: 0.0118 AC: 470 AN: 39696

South Asian (SAS) AF: 0.179 AC: 15460 AN: 86238

European-Finnish (FIN) AF: 0.188 AC: 10022 AN: 53414

Middle Eastern (MID) AF: 0.337 AC: 1942 AN: 5766

European-Non Finnish (NFE) AF: 0.339 AC: 375955 AN: 1110330

Other (OTH) AF: 0.295 AC: 17821 AN: 60344

GnomAD4 genome AF: 0.262 AC: 39873 AN: 152144 Hom.: 5876 Cov.: 32 AF XY: 0.254 AC XY: 18879 AN XY: 74372

African (AFR) AF: 0.168 AC: 6969 AN: 41520

American (AMR) AF: 0.354 AC: 5417 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1042 AN: 3468

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5180

South Asian (SAS) AF: 0.169 AC: 816 AN: 4820

European-Finnish (FIN) AF: 0.183 AC: 1936 AN: 10564

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22607 AN: 67978

Other (OTH) AF: 0.294 AC: 622 AN: 2114

Alfa AF: 0.315 Hom.: 33169

Bravo AF: 0.276

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Intellectual disability, autosomal dominant 6 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy, 27 (1)
-	-	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	-0.77
CADD	Benign	6.1
DANN	Benign	0.63
PhyloP100		0.026
Mutation Taster		=93/7	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: rs1805482; hg19: chr12-13764774; COSMIC: COSV74206213; COSMIC: COSV74206213;