chr12-13570193-T-C

Variant names:

• chr12-13570193-T-C
• rs1806194
• NM_000834.5:c.2172-176A>G

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.2172-176A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,162 control chromosomes in the GnomAD database, including 8,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (8701 hom., cov: 33)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.722
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-13570193-T-C is Benign according to our data. Variant chr12-13570193-T-C is described in ClinVar as Benign. ClinVar VariationId is 681647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.2172-176A>G		intron_variant	Intron 11 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.2172-176A>G		intron_variant	Intron 12 of 14		NP_001400921.1
GRIN2B	XM_005253351.3	c.-43-176A>G		intron_variant	Intron 1 of 3		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.2172-176A>G		intron_variant	Intron 11 of 13	1	NM_000834.5	ENSP00000477455.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45600 AN: 152044 Hom.: 8693 Cov.: 33

Gnomad AFR AF: 0.0834

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.344

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

GnomAD4 genome AF: 0.300 AC: 45612 AN: 152162 Hom.: 8701 Cov.: 33 AF XY: 0.297 AC XY: 22094 AN XY: 74390

African (AFR) AF: 0.0832 AC: 3454 AN: 41518

American (AMR) AF: 0.398 AC: 6082 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1436 AN: 3468

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5186

South Asian (SAS) AF: 0.227 AC: 1095 AN: 4824

European-Finnish (FIN) AF: 0.343 AC: 3627 AN: 10568

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28629 AN: 67988

Other (OTH) AF: 0.343 AC: 725 AN: 2112

Alfa AF: 0.387 Hom.: 51831

Bravo AF: 0.298

Asia WGS AF: 0.137 AC: 479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1806194; hg19: chr12-13723127;