rs147373250

Positions:

• chr12-13608762-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000834.5(GRIN2B):​c.1851C>T​(p.Ser617=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,614,048 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (3 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.531

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 12-13608762-G-A is Benign according to our data. Variant chr12-13608762-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr12-13608762-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000486 (74/152228) while in subpopulation SAS AF= 0.00187 (9/4814). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.1851C>T	p.Ser617=	synonymous_variant	10/14	ENST00000609686.4
LOC105369668	XR_001749013.2	n.342+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1851C>T	p.Ser617=	synonymous_variant	10/14	1	NM_000834.5	P1
	ENST00000652867.1	n.203-6336G>A		intron_variant, non_coding_transcript_variant
GRIN2B	ENST00000628166.2	n.111C>T		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000656 AC: 165 AN: 251446 Hom.: 3 AF XY: 0.000817 AC XY: 111 AN XY: 135890

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000799 AC: 1168 AN: 1461820 Hom.: 3 Cov.: 32 AF XY: 0.000831 AC XY: 604 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000801

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74438

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000671 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2015	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 13, 2015	- -

Intellectual disability, autosomal dominant 6 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Aug 03, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2017

This alteration is classified as likely 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

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147373250; hg19: chr12-13761696; COSMIC: COSV104725288; COSMIC: COSV104725288;