rs1805247

Variant names:

• chr12-13563041-A-G
• rs1805247
• NM_000834.5:c.4197T>C

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.4197T>C​(p.His1399His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,904 control chromosomes in the GnomAD database, including 12,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3007 hom., cov: 33)
  • Exomes 𝑓: 0.10 (9505 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.0850
• Publications: 37 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: Ambry Genetics, ClinGen
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.56).
• BP6: Variant 12-13563041-A-G is Benign according to our data. Variant chr12-13563041-A-G is described in ClinVar as Benign. ClinVar VariationId is 98432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.085 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 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.4197T>C	p.His1399His	synonymous	Exon 14 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.4197T>C	p.His1399His	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.4197T>C	p.His1399His	synonymous	Exon 14 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.4197T>C	p.His1399His	synonymous	Exon 15 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000637214.1	TSL:5	c.69+45562T>C		intron	N/A	ENSP00000489997.1	A0A1B0GU78

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25199 AN: 152054 Hom.: 2982 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0845

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.130 AC: 32584 AN: 251330 AF XY: 0.129

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.0872

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0868

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0999 AC: 146040 AN: 1461732 Hom.: 9505 Cov.: 34 AF XY: 0.103 AC XY: 74824 AN XY: 727142

African (AFR) AF: 0.343 AC: 11494 AN: 33476

American (AMR) AF: 0.117 AC: 5210 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 2265 AN: 26134

East Asian (EAS) AF: 0.204 AC: 8112 AN: 39694

South Asian (SAS) AF: 0.204 AC: 17616 AN: 86252

European-Finnish (FIN) AF: 0.111 AC: 5908 AN: 53392

Middle Eastern (MID) AF: 0.120 AC: 694 AN: 5768

European-Non Finnish (NFE) AF: 0.0790 AC: 87872 AN: 1111910

Other (OTH) AF: 0.114 AC: 6869 AN: 60388

GnomAD4 genome AF: 0.166 AC: 25263 AN: 152172 Hom.: 3007 Cov.: 33 AF XY: 0.166 AC XY: 12353 AN XY: 74418

African (AFR) AF: 0.333 AC: 13835 AN: 41500

American (AMR) AF: 0.120 AC: 1839 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 293 AN: 3466

East Asian (EAS) AF: 0.182 AC: 936 AN: 5154

South Asian (SAS) AF: 0.214 AC: 1029 AN: 4814

European-Finnish (FIN) AF: 0.106 AC: 1120 AN: 10616

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0845 AC: 5747 AN: 68006

Other (OTH) AF: 0.152 AC: 320 AN: 2112

Alfa AF: 0.113 Hom.: 2587

Bravo AF: 0.173

Asia WGS AF: 0.199 AC: 693 AN: 3478

EpiCase AF: 0.0846

EpiControl AF: 0.0799

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	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	-0.56
CADD	Benign	2.2
DANN	Benign	0.51
PhyloP100		-0.085
Mutation Taster		=94/6	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: rs1805247; hg19: chr12-13715975; COSMIC: COSV74205188; COSMIC: COSV74205188;