NM_000834.5:c.1126-73A>G

Variant names:

• chr12-13616730-T-C
• rs1805199
• NM_000834.5:c.1126-73A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000834.5(GRIN2B):​c.1126-73A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,189,670 control chromosomes in the GnomAD database, including 398,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45053 hom., cov: 33)
  • Exomes 𝑓: 0.82 (353919 hom.)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.704

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]

ENSG00000287928 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-13616730-T-C is Benign according to our data. Variant chr12-13616730-T-C is described in ClinVar as [Benign]. Clinvar id is 1290979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1126-73A>G		intron_variant	Intron 5 of 13	ENST00000609686.4	NP_000825.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1126-73A>G		intron_variant	Intron 5 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.2	c.1126-73A>G		intron_variant	Intron 6 of 7	5		ENSP00000486677.3
ENSG00000287928	ENST00000652867.1	n.331+1504T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115608 AN: 152066 Hom.: 45033 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.824 AC: 854632 AN: 1037486 Hom.: 353919 AF XY: 0.825 AC XY: 441148 AN XY: 534928

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.894

Gnomad4 ASJ exome AF: 0.745

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.851

Gnomad4 FIN exome AF: 0.864

Gnomad4 NFE exome AF: 0.817

Gnomad4 OTH exome AF: 0.817

GnomAD4 genome AF: 0.760 AC: 115675 AN: 152184 Hom.: 45053 Cov.: 33 AF XY: 0.767 AC XY: 57072 AN XY: 74392

Gnomad4 AFR AF: 0.581

Gnomad4 AMR AF: 0.828

Gnomad4 ASJ AF: 0.745

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.855

Gnomad4 FIN AF: 0.863

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.770

Alfa AF: 0.801 Hom.: 55967

Bravo AF: 0.752

Asia WGS AF: 0.910 AC: 3158 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 86. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.58

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: rs1805199; hg19: chr12-13769664;