rs201405157

chr12-13563590-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000834.5(GRIN2B):c.3648C>T(p.Arg1216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.323

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-13563590-G-A is Benign according to our data. Variant chr12-13563590-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 98433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.323 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000164 (25/152300) while in subpopulation AFR AF= 0.000553 (23/41562). AF 95% confidence interval is 0.000378. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.3648C>T	p.Arg1216=	synonymous_variant	14/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.3648C>T	p.Arg1216=	synonymous_variant	15/15
GRIN2B	XM_005253351.3	c.1434C>T	p.Arg478=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.3648C>T	p.Arg1216=	synonymous_variant	14/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+45013C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 250876 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135590

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727204

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74456

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000227

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	- -
not provided, no classification provided	literature only	Psychiatry Genetics Yale University	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 20, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.9
Dann	Benign	0.69

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: rs201405157; hg19: chr12-13716524;