12-13908635-G-T

Variant names:

• chr12-13908635-G-T
• rs11055681
• NM_000834.5:c.-18-42409C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000834.5(GRIN2B):​c.-18-42409C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,024 control chromosomes in the GnomAD database, including 2,297 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2297 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 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.-18-42409C>A		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.-18-42409C>A		intron	N/A	NP_001400921.1	A0A8D9PHB2
	GRIN2B	NM_001413993.1		c.-18-42409C>A		intron	N/A	NP_001400922.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.-18-42409C>A		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.-18-42409C>A		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000627535.2	TSL:5	c.-18-42409C>A		intron	N/A	ENSP00000486411.1	A0A0D9SFA0

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25190 AN: 151906 Hom.: 2295 Cov.: 32

Gnomad AFR AF: 0.0902

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.179

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.166 AC: 25209 AN: 152024 Hom.: 2297 Cov.: 32 AF XY: 0.169 AC XY: 12529 AN XY: 74302

African (AFR) AF: 0.0903 AC: 3749 AN: 41518

American (AMR) AF: 0.192 AC: 2927 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3472

East Asian (EAS) AF: 0.186 AC: 957 AN: 5136

South Asian (SAS) AF: 0.193 AC: 925 AN: 4804

European-Finnish (FIN) AF: 0.215 AC: 2264 AN: 10550

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13186 AN: 67962

Other (OTH) AF: 0.181 AC: 382 AN: 2112

Alfa AF: 0.183 Hom.: 1631

Bravo AF: 0.161

Asia WGS AF: 0.172 AC: 599 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		2.9
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: rs11055681; hg19: chr12-14061569;