rs77029288

Variant names:

• chr16-9763237-T-C
• rs77029288
• NM_001134407.3:c.4307A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-9763237-T-C
• chr16-9763237-T-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001134407.3(GRIN2A):​c.4307A>G​(p.Asn1436Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00103 in 1,613,986 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 4.20
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026804864).
• BP6: Variant 16-9763237-T-C is Benign according to our data. Variant chr16-9763237-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205683.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000664 (101/152214) while in subpopulation NFE AF = 0.00118 (80/68046). AF 95% confidence interval is 0.000967. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4307A>G	p.Asn1436Ser	missense	Exon 13 of 13	NP_001127879.1	Q12879-1
	GRIN2A	NM_000833.5		c.4307A>G	p.Asn1436Ser	missense	Exon 14 of 14	NP_000824.1	Q12879-1
	GRIN2A	NM_001134408.2		c.*118A>G		3_prime_UTR	Exon 14 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.4307A>G	p.Asn1436Ser	missense	Exon 13 of 13	ENSP00000332549.3	Q12879-1
	GRIN2A	ENST00000396573.6	TSL:1	c.4307A>G	p.Asn1436Ser	missense	Exon 14 of 14	ENSP00000379818.2	Q12879-1
	GRIN2A	ENST00000562109.5	TSL:1	c.*118A>G		3_prime_UTR	Exon 14 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000617 AC: 155 AN: 251166 AF XY: 0.000626

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00107 AC: 1562 AN: 1461772 Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 747 AN XY: 727192

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00130 AC: 1450 AN: 1111920

Other (OTH) AF: 0.000662 AC: 40 AN: 60390

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74368

African (AFR) AF: 0.000193 AC: 8 AN: 41456

American (AMR) AF: 0.000524 AC: 8 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000827 Hom.: 0

Bravo AF: 0.000586

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	Landau-Kleffner syndrome (5)
-	1	2	not provided (3)
-	1	2	not specified (3)
-	-	1	GRIN2A-related complex neurodevelopmental disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.72
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.10
Sift	Benign	0.72	T
Sift4G	Benign	0.95	T
Polyphen		0.016	B
Vest4		0.032
MVP		0.64
MPC		0.20
ClinPred		0.012	T
GERP RS		4.7
Varity_R		0.072
gMVP		0.23
Mutation Taster		=82/18	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: rs77029288; hg19: chr16-9857094; COSMIC: COSV99043460; COSMIC: COSV99043460;