rs1555103646

Variant names:

• chr12-13569964-C-A
• rs1555103646
• NM_000834.5:c.2225G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000834.5(GRIN2B):​c.2225G>T​(p.Arg742Ile) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 170) in uniprot entity NMDE2_HUMAN there are 37 pathogenic changes around while only 0 benign (100%) in NM_000834.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GRIN2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 118 curated benign missense variants. Gene score misZ: 5.4168 (above the threshold of 3.09). Trascript score misZ: 7.3273 (above the threshold of 3.09). GenCC associations: The gene is linked to autism susceptibility 1, developmental and epileptic encephalopathy, 27, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, West syndrome, intellectual disability, autosomal dominant 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 12-13569964-C-A is Pathogenic according to our data. Variant chr12-13569964-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523382.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.2225G>T	p.Arg742Ile	missense_variant	Exon 12 of 14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.2225G>T	p.Arg742Ile	missense_variant	Exon 13 of 15		NP_001400921.1
GRIN2B	XM_005253351.3	c.11G>T	p.Arg4Ile	missense_variant	Exon 2 of 4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.2225G>T	p.Arg742Ile	missense_variant	Exon 12 of 14	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000637214.1	c.69+38639G>T		intron_variant	Intron 1 of 1	5		ENSP00000489997.1
GRIN2B	ENST00000628166.2	n.485G>T		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical behavior;C0036572:Seizure;C0856975:Autistic behavior;C3714756:Intellectual disability Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.63
MutPred		0.78		Loss of solvent accessibility (P = 0.0611);
MVP		0.98
MPC		2.8
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555103646; hg19: chr12-13722898;