rs61731465

chr16-9764645-C-Gchr16-9764645-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134407.3(GRIN2A):c.2899G>C(p.Val967Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,614,128 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (61 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.869

Genes affected

GRIN2A (HGNC:4585): (glutamate ionotropic receptor NMDA type subunit 2A) This gene encodes a member of the glutamate-gated ion channel protein family. The encoded protein is an N-methyl-D-aspartate (NMDA) receptor subunit. NMDA receptors are both ligand-gated and voltage-dependent, and are involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. These receptors are permeable to calcium ions, and activation results in a calcium influx into post-synaptic cells, which results in the activation of several signaling cascades. Disruption of this gene is associated with focal epilepsy and speech disorder with or without cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0044463575).
• BP6: Variant 16-9764645-C-G is Benign according to our data. Variant chr16-9764645-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-9764645-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00516 (785/152272) while in subpopulation NFE AF= 0.00822 (559/68018). AF 95% confidence interval is 0.00765. There are 2 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 785 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.2899G>C	p.Val967Leu	missense_variant	13/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2899G>C	p.Val967Leu	missense_variant	13/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152154 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00822

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00583 AC: 1466 AN: 251404 Hom.: 7 AF XY: 0.00622 AC XY: 845 AN XY: 135874

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00790

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00753 AC: 11013 AN: 1461856 Hom.: 61 Cov.: 34 AF XY: 0.00745 AC XY: 5415 AN XY: 727232

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00769

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00850

Gnomad4 OTH exome AF: 0.00593

GnomAD4 genome AF: 0.00516 AC: 785 AN: 152272 Hom.: 2 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74456

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.00822

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00641 Hom.: 2

Bravo AF: 0.00492

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00387 AC: 17

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00573 AC: 696

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jul 11, 2017	BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2020	- -

Landau-Kleffner syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GRIN2A: BP4, BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	16
Dann	Benign	0.51
DEOGEN2	Benign	0.27	T;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.73	D
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.060	N;.;N;N
MutationTaster	Benign	0.69	N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.32	N;.;N;N
REVEL	Benign	0.032
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.91	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.049
MutPred		0.47		Loss of methylation at K972 (P = 0.0967);.;Loss of methylation at K972 (P = 0.0967);Loss of methylation at K972 (P = 0.0967);
MVP		0.17
MPC		0.25
ClinPred		0.0015	T
GERP RS		4.5
Varity_R		0.072
gMVP		0.31

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: rs61731465; hg19: chr16-9858502; COSMIC: COSV105221349; COSMIC: COSV105221349;