16-9764316-G-T

Variant names:

• chr16-9764316-G-T
• rs61758995
• NM_001134407.3:c.3228C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134407.3(GRIN2A):​c.3228C>A​(p.Asn1076Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,614,114 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1076S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (29 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.40
• Publications: 24 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055758953).
• BP6: Variant 16-9764316-G-T is Benign according to our data. Variant chr16-9764316-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00447 (681/152250) while in subpopulation AMR AF = 0.00831 (127/15290). AF 95% confidence interval is 0.00713. There are 3 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.3228C>A	p.Asn1076Lys	missense	Exon 13 of 13	NP_001127879.1	Q12879-1
	GRIN2A	NM_000833.5		c.3228C>A	p.Asn1076Lys	missense	Exon 14 of 14	NP_000824.1	Q12879-1
	GRIN2A	NM_001134408.2		c.3228C>A	p.Asn1076Lys	missense	Exon 13 of 14	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.3228C>A	p.Asn1076Lys	missense	Exon 13 of 13	ENSP00000332549.3	Q12879-1
	GRIN2A	ENST00000396573.6	TSL:1	c.3228C>A	p.Asn1076Lys	missense	Exon 14 of 14	ENSP00000379818.2	Q12879-1
	GRIN2A	ENST00000562109.5	TSL:1	c.3228C>A	p.Asn1076Lys	missense	Exon 13 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152132 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00832

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00421 AC: 1059 AN: 251398 AF XY: 0.00423

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00567 AC: 8288 AN: 1461864 Hom.: 29 Cov.: 34 AF XY: 0.00545 AC XY: 3965 AN XY: 727240

African (AFR) AF: 0.000896 AC: 30 AN: 33478

American (AMR) AF: 0.00257 AC: 115 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86258

European-Finnish (FIN) AF: 0.00268 AC: 143 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.00673 AC: 7484 AN: 1111984

Other (OTH) AF: 0.00483 AC: 292 AN: 60396

GnomAD4 genome AF: 0.00447 AC: 681 AN: 152250 Hom.: 3 Cov.: 32 AF XY: 0.00465 AC XY: 346 AN XY: 74430

African (AFR) AF: 0.00116 AC: 48 AN: 41558

American (AMR) AF: 0.00831 AC: 127 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00650 AC: 442 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00595 Hom.: 11

Bravo AF: 0.00479

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00435 AC: 528

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00634

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Landau-Kleffner syndrome (4)
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.46		Gain of MoRF binding (P = 0.0255)
MVP		0.71
MPC		0.72
ClinPred		0.014	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.20
Mutation Taster		=91/9	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: rs61758995; hg19: chr16-9858173; COSMIC: COSV100409179;