16-9763717-G-C

Variant names:

• chr16-9763717-G-C
• rs145063086
• NM_001134407.3:c.3827C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134407.3(GRIN2A):​c.3827C>G​(p.Ala1276Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000926 in 1,614,068 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 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).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (3 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 5.81
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0374074).
• BP6: Variant 16-9763717-G-C is Benign according to our data. Variant chr16-9763717-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205679.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000663 (101/152280) while in subpopulation NFE AF = 0.00122 (83/68014). AF 95% confidence interval is 0.00101. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.3827C>G	p.Ala1276Gly	missense	Exon 13 of 13	NP_001127879.1
	GRIN2A	NM_000833.5		c.3827C>G	p.Ala1276Gly	missense	Exon 14 of 14	NP_000824.1
	GRIN2A	NM_001134408.2		c.3772+55C>G		intron	N/A	NP_001127880.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.3827C>G	p.Ala1276Gly	missense	Exon 13 of 13	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.3827C>G	p.Ala1276Gly	missense	Exon 14 of 14	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.3772+55C>G		intron	N/A	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000573 AC: 144 AN: 251356 AF XY: 0.000523

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000953 AC: 1393 AN: 1461788 Hom.: 3 Cov.: 33 AF XY: 0.000905 AC XY: 658 AN XY: 727208

African (AFR) AF: 0.000299 AC: 10 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53388

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

European-Non Finnish (NFE) AF: 0.00118 AC: 1315 AN: 1111958

Other (OTH) AF: 0.000497 AC: 30 AN: 60392

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74466

African (AFR) AF: 0.000313 AC: 13 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000951 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	Landau-Kleffner syndrome (3)
-	1	-	Focal epilepsy (1)
-	-	1	GRIN2A-related complex neurodevelopmental disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.23	N
PhyloP100		5.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.089
Sift	Benign	0.28	T
Sift4G	Benign	0.71	T
Polyphen		0.52	P
Vest4		0.048
MVP		0.41
MPC		0.25
ClinPred		0.056	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.25
Mutation Taster		=96/4	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: rs145063086; hg19: chr16-9857574; COSMIC: COSV58049752;