chr12-13564162-C-T

Position:

chr12-13564162-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The ENST00000609686.4(GRIN2B):c.3076G>A(p.Gly1026Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000263 in 1,614,052 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1026G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

GRIN2B
ENST00000609686.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 5.23

Variant links:

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]

GRIN2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRIN2B. . Gene score misZ 5.4168 (greater than the threshold 3.09). Trascript score misZ 7.3273 (greater than threshold 3.09). GenCC has associacion of gene with autism susceptibility 1, developmental and epileptic encephalopathy, 27, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, West syndrome, intellectual disability, autosomal dominant 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.16046378).

BP6

Variant 12-13564162-C-T is Benign according to our data. Variant chr12-13564162-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205716.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2, Likely_benign=4}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152168) while in subpopulation SAS AF= 0.000415 (2/4820). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRIN2B	NM_000834.5 linkuse as main transcript	c.3076G>A	p.Gly1026Ser	missense_variant	14/14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1 linkuse as main transcript	c.3076G>A	p.Gly1026Ser	missense_variant	15/15		NP_001400921.1
GRIN2B	XM_005253351.3 linkuse as main transcript	c.862G>A	p.Gly288Ser	missense_variant	4/4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4 linkuse as main transcript	c.3076G>A	p.Gly1026Ser	missense_variant	14/14	1	NM_000834.5	ENSP00000477455	P1
GRIN2B	ENST00000637214.1 linkuse as main transcript	c.69+44441G>A		intron_variant		5		ENSP00000489997

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251428

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000277

AC:

405

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000312

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000199

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 27818011, 22986046, 22833210) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2016	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 19, 2024

Variant summary: GRIN2B c.3076G>A (p.Gly1026Ser) results in a non-conservative amino acid change located in the N-methyl D-aspartate receptor 2B3 C-terminus domain (IPR018884) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251428 control chromosomes. c.3076G>A has been reported in the literature in at least one individual affected with autism spectrum disorder, without evidence for causation (e.g. Tarabeux_2011). This report does not provide unequivocal conclusions about association of the variant with Mental Retardation, Autosomal Dominant 6. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22833210). ClinVar contains an entry for this variant (Variation ID: 205716). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

GRIN2B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 27

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.35

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0045

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

Sift4G

Benign

0.74

Polyphen

0.64

Vest4

0.34

MVP

0.91

MPC

2.1

ClinPred

0.19

GERP RS

5.5

Varity_R

0.34

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over