rs1057519004

Variant names:

• chr12-13611833-C-T
• rs1057519004
• NM_000834.5:c.1672G>A
• GRIN2B p.Val558Ile

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP3 PP5_Very_Strong

The NM_000834.5(GRIN2B):​c.1672G>A​(p.Val558Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004030621: Published functional studies demonstrate that V558I affected some GluN2B containing NMDAR channel property (Vyklivky et al., 2018)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V558V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 7.87
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004030621: Published functional studies demonstrate that V558I affected some GluN2B containing NMDAR channel property (Vyklivky et al., 2018); SCV004570857: Experimental studies have shown that this missense change affects GRIN2B function (PMID: 28377535, 29681796).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000834.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 12-13611833-C-T is Pathogenic according to our data. Variant chr12-13611833-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1672G>A	p.Val558Ile	missense	Exon 9 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.1672G>A	p.Val558Ile	missense	Exon 10 of 15	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.1672G>A	p.Val558Ile	missense	Exon 9 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.1672G>A	p.Val558Ile	missense	Exon 10 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000714048.1		n.1672G>A		non_coding_transcript_exon	Exon 9 of 13	ENSP00000519339.1	A0AAQ5BH89

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461432 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727058

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111590

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Intellectual disability, autosomal dominant 6 (3)
1	-	-	Complex neurodevelopmental disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	intellectual deficiency (1)
1	-	-	Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 (1)
1	-	-	not provided (1)
-	1	-	not specified (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.014	D
Varity_R		0.48
gMVP		0.89
Mutation Taster		=47/53	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519004;

hg19: chr12-13764767;

COSMIC: COSV74206831;

COSMIC: COSV74206831;