16-9763690-C-A

Variant names:

• chr16-9763690-C-A
• rs367543132
• NM_001134407.3:c.3854G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001134407.3(GRIN2A):​c.3854G>T​(p.Arg1285Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/22 in silico tools predict 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. R1285K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.19
• Publications: 5 publications found

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]

GRIN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Landau-Kleffner syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• continuous spikes and waves during sleep

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• rolandic epilepsy-speech dyspraxia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• self-limited epilepsy with centrotemporal spikes

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 16-9763690-C-A is Benign according to our data. Variant chr16-9763690-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 579885.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134407.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	NM_001134407.3	MANE Select	c.3854G>T	p.Arg1285Met	missense	Exon 13 of 13	NP_001127879.1	Q12879-1
	GRIN2A	NM_000833.5		c.3854G>T	p.Arg1285Met	missense	Exon 14 of 14	NP_000824.1	Q12879-1
	GRIN2A	NM_001134408.2		c.3772+82G>T		intron	N/A	NP_001127880.1	Q12879-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.3854G>T	p.Arg1285Met	missense	Exon 13 of 13	ENSP00000332549.3	Q12879-1
	GRIN2A	ENST00000396573.6	TSL:1	c.3854G>T	p.Arg1285Met	missense	Exon 14 of 14	ENSP00000379818.2	Q12879-1
	GRIN2A	ENST00000562109.5	TSL:1	c.3772+82G>T		intron	N/A	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251360 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461756 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111984

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Landau-Kleffner syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.74		Loss of MoRF binding (P = 0.0124)
MVP		0.34
MPC		0.72
ClinPred		0.23	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.47
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs367543132; hg19: chr16-9857547;