rs1805246

chr12-13563020-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000834.5(GRIN2B):c.4218C>T(p.Phe1406=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0367 in 1,613,930 control chromosomes in the GnomAD database, including 1,338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (98 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1240 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 4.20

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-13563020-G-A is Benign according to our data. Variant chr12-13563020-G-A is described in ClinVar as [Benign]. Clinvar id is 98431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13563020-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.4218C>T	p.Phe1406=	synonymous_variant	14/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.4218C>T	p.Phe1406=	synonymous_variant	15/15
GRIN2B	XM_005253351.3	c.2004C>T	p.Phe668=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.4218C>T	p.Phe1406=	synonymous_variant	14/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+45583C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4328 AN: 152212 Hom.: 99 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0400

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.0367 AC: 9228 AN: 251330 Hom.: 247 AF XY: 0.0389 AC XY: 5291 AN XY: 135864

Gnomad AFR exome AF: 0.00635

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.0874

Gnomad SAS exome AF: 0.0702

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0376 AC: 54901 AN: 1461600 Hom.: 1240 Cov.: 32 AF XY: 0.0387 AC XY: 28108 AN XY: 727056

Gnomad4 AFR exome AF: 0.00603

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0220

Gnomad4 EAS exome AF: 0.0704

Gnomad4 SAS exome AF: 0.0689

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0394

GnomAD4 genome AF: 0.0284 AC: 4326 AN: 152330 Hom.: 98 Cov.: 33 AF XY: 0.0280 AC XY: 2085 AN XY: 74488

Gnomad4 AFR AF: 0.00695

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0865

Gnomad4 SAS AF: 0.0759

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0400

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0332 Hom.: 40

Bravo AF: 0.0258

Asia WGS AF: 0.0720 AC: 249 AN: 3478

EpiCase AF: 0.0356

EpiControl AF: 0.0333

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Other:1

not provided, no classification provided

literature only

Psychiatry Genetics Yale University

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	12
Dann	Benign	0.73

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: rs1805246; hg19: chr12-13715954;