rs369878342

chr16-9764039-G-Achr16-9764039-G-Cchr16-9764039-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001134407.3(GRIN2A):c.3505C>T(p.Arg1169Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1169Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (1 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.57

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.19229329).
• BP6: Variant 16-9764039-G-A is Benign according to our data. Variant chr16-9764039-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 576520.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.3505C>T	p.Arg1169Trp	missense_variant	13/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.3505C>T	p.Arg1169Trp	missense_variant	13/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251286 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461738 Hom.: 1 Cov.: 33 AF XY: 0.0000784 AC XY: 57 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74446

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000953 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Landau-Kleffner syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.;D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;M
MutationTaster	Benign	0.85	D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.026	D;.;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.34
MVP		0.42
MPC		0.90
ClinPred		0.24	T
GERP RS		0.29
Varity_R		0.080
gMVP		0.55

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: rs369878342; hg19: chr16-9857896; COSMIC: COSV58036726; COSMIC: COSV58036726;