rs1060503160

Variant names:

• chr12-13866186-C-G
• rs1060503160
• NM_000834.5:c.23G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-13866186-C-G
• chr12-13866186-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000834.5(GRIN2B):​c.23G>C​(p.Cys8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C8Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19788611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.23G>C	p.Cys8Ser	missense_variant	Exon 3 of 14	ENST00000609686.4	NP_000825.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.23G>C	p.Cys8Ser	missense_variant	Exon 3 of 14	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.23G>C	p.Cys8Ser	missense_variant	Exon 4 of 15	5		ENSP00000486677.3
GRIN2B	ENST00000627535.2	c.23G>C	p.Cys8Ser	missense_variant	Exon 3 of 3	5		ENSP00000486411.1
GRIN2B	ENST00000714048.1	n.23G>C		non_coding_transcript_exon_variant	Exon 3 of 13			ENSP00000519339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Uncertain:1

Sep 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GRIN2B-related disease. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This sequence change replaces cysteine with serine at codon 8 of the GRIN2B protein (p.Cys8Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T;.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.067	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.30
MutPred		0.64		Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);
MVP		0.25
MPC		1.4
ClinPred		0.25	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.54
Mutation Taster		=79/21	polymorphism

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: rs1060503160; hg19: chr12-14019120;