rs1805199

Variant names:

• chr12-13616730-T-C
• rs1805199
• NM_000834.5:c.1126-73A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-13616730-T-C
• chr12-13616730-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000834.5(GRIN2B):​c.1126-73A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,189,670 control chromosomes in the GnomAD database, including 398,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45053 hom., cov: 33)
  • Exomes 𝑓: 0.82 (353919 hom.)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.704
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-13616730-T-C is Benign according to our data. Variant chr12-13616730-T-C is described in ClinVar as Benign. ClinVar VariationId is 1290979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 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.1126-73A>G		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.1126-73A>G		intron	N/A	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.1126-73A>G		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.1126-73A>G		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	ENSG00000287928	ENST00000652867.1		n.331+1504T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115608 AN: 152066 Hom.: 45033 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.824 AC: 854632 AN: 1037486 Hom.: 353919 AF XY: 0.825 AC XY: 441148 AN XY: 534928

African (AFR) AF: 0.580 AC: 14659 AN: 25276

American (AMR) AF: 0.894 AC: 39409 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 17498 AN: 23500

East Asian (EAS) AF: 0.990 AC: 37464 AN: 37830

South Asian (SAS) AF: 0.851 AC: 66010 AN: 77550

European-Finnish (FIN) AF: 0.864 AC: 44927 AN: 52000

Middle Eastern (MID) AF: 0.791 AC: 3904 AN: 4936

European-Non Finnish (NFE) AF: 0.817 AC: 592815 AN: 725870

Other (OTH) AF: 0.817 AC: 37946 AN: 46434

GnomAD4 genome AF: 0.760 AC: 115675 AN: 152184 Hom.: 45053 Cov.: 33 AF XY: 0.767 AC XY: 57072 AN XY: 74392

African (AFR) AF: 0.581 AC: 24097 AN: 41488

American (AMR) AF: 0.828 AC: 12660 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2585 AN: 3472

East Asian (EAS) AF: 0.991 AC: 5135 AN: 5182

South Asian (SAS) AF: 0.855 AC: 4123 AN: 4822

European-Finnish (FIN) AF: 0.863 AC: 9148 AN: 10598

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55272 AN: 68012

Other (OTH) AF: 0.770 AC: 1629 AN: 2116

Alfa AF: 0.796 Hom.: 79488

Bravo AF: 0.752

Asia WGS AF: 0.910 AC: 3158 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.58
PhyloP100		-0.70
Mutation Taster		=100/0	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: rs1805199; hg19: chr12-13769664;