rs78631453

chr16-9938544-G-Achr16-9938544-G-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.422C>T(p.Thr141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,603,046 control chromosomes in the GnomAD database, including 7 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T141K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.87

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=0.008182764).
• BP6: Variant 16-9938544-G-A is Benign according to our data. Variant chr16-9938544-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 205638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-9938544-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000926 (141/152314) while in subpopulation NFE AF= 0.00159 (108/68022). AF 95% confidence interval is 0.00135. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.422C>T	p.Thr141Met	missense_variant	3/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.422C>T	p.Thr141Met	missense_variant	3/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes AF: 0.000926 AC: 141 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00111 AC: 260 AN: 235002 Hom.: 1 AF XY: 0.00114 AC XY: 147 AN XY: 128780

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00363

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00102

Gnomad FIN exome AF: 0.000367

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.000838

GnomAD4 exome AF: 0.00156 AC: 2266 AN: 1450732 Hom.: 7 Cov.: 31 AF XY: 0.00160 AC XY: 1152 AN XY: 722104

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.000279

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74476

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00187 Hom.: 3

Bravo AF: 0.000963

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00154 AC: 13

ExAC AF: 0.00104 AC: 126

EpiCase AF: 0.00180

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Landau-Kleffner syndrome Benign:4

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 29, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GRIN2A: BP4, BS1 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2016	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	Genetic Services Laboratory, University of Chicago	Nov 19, 2015	- -

GRIN2A-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2019

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). -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Benign	0.86
DEOGEN2	Benign	0.31	T;.;.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;.;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.87	N;.;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.21	T;.;T;T;.
Sift4G	Benign	0.29	T;T;T;T;.
Polyphen		0.016	B;.;.;B;.
Vest4		0.23
MVP		0.64
MPC		0.65
ClinPred		0.0050	T
GERP RS		1.6
Varity_R		0.032
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78631453; hg19: chr16-10032401; COSMIC: COSV100410848;