12-13719110-G-T

Variant names:

• chr12-13719110-G-T
• rs2268118
• NM_000834.5:c.1010+34207C>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.1010+34207C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 151,774 control chromosomes in the GnomAD database, including 774 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 0.094 (774 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1010+34207C>A		intron_variant	Intron 4 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.1010+34207C>A		intron_variant	Intron 5 of 14		NP_001400921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1010+34207C>A		intron_variant	Intron 4 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.1010+34207C>A		intron_variant	Intron 5 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000714048.1	n.1010+34207C>A		intron_variant	Intron 4 of 12			ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14259 AN: 151656 Hom.: 761 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0956

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0862

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0762

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

GnomAD4 genome AF: 0.0943 AC: 14313 AN: 151774 Hom.: 774 Cov.: 32 AF XY: 0.0961 AC XY: 7124 AN XY: 74148

African (AFR) AF: 0.136 AC: 5639 AN: 41416

American (AMR) AF: 0.0965 AC: 1468 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3466

East Asian (EAS) AF: 0.181 AC: 923 AN: 5094

South Asian (SAS) AF: 0.107 AC: 516 AN: 4816

European-Finnish (FIN) AF: 0.0862 AC: 910 AN: 10552

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

European-Non Finnish (NFE) AF: 0.0626 AC: 4252 AN: 67900

Other (OTH) AF: 0.0816 AC: 172 AN: 2108

Alfa AF: 0.0688 Hom.: 515

Bravo AF: 0.0936

Asia WGS AF: 0.163 AC: 566 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.41
PhyloP100		-0.38
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: rs2268118; hg19: chr12-13872044;