Genetic Variant GRIN2A:p.Asn976Ser (chr16-9764616-ATT-GGA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001134407.3(GRIN2A):c.2926_2928delAATinsTCC (p.Asn976Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.39). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N976K: Uncertain_significance (ClinVar VariationId 4750046, 1 star); p.N976S: Likely_benign (ClinVar VariationId 264707, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 32)

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.39

Publications

0 publications found

Variant links:

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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
continuous spikes and waves during sleep
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
developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

GRIN2A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001134407.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
GRIN2A NM_001134407.3	MANE Select	c.2926_2928delAATinsTCC p.Asn976Ser	missense	N/A	Prot: NP_001127879.1 UniProt: Q12879-1
GRIN2A NM_000833.5		c.2926_2928delAATinsTCC p.Asn976Ser	missense	N/A	Prot: NP_000824.1 UniProt: Q12879-1
GRIN2A NM_001134408.2		c.2926_2928delAATinsTCC p.Asn976Ser	missense	N/A	Prot: NP_001127880.1 UniProt: Q12879-2

GRIN2A NM_001134407.3

MANE Select

HGVSc / HGVSpc.2926_2928delAATinsTCCp.Asn976Ser

Exon rankN/A

missense

Prot: NP_001127879.1UniProt: Q12879-1

GRIN2A NM_000833.5

HGVSc / HGVSpc.2926_2928delAATinsTCCp.Asn976Ser

Exon rankN/A

missense

Prot: NP_000824.1UniProt: Q12879-1

GRIN2A NM_001134408.2

HGVSc / HGVSpc.2926_2928delAATinsTCCp.Asn976Ser

Exon rankN/A

missense

Prot: NP_001127880.1UniProt: Q12879-2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
GRIN2A ENST00000330684.4	TSL:1MANE Select	c.2926_2928delAATinsTCC p.Asn976Ser	missense	N/A	Prot: ENSP00000332549.3 UniProt: Q12879-1
GRIN2A ENST00000396573.6	TSL:1	c.2926_2928delAATinsTCC p.Asn976Ser	missense	N/A	Prot: ENSP00000379818.2 UniProt: Q12879-1
GRIN2A ENST00000562109.5	TSL:1	c.2926_2928delAATinsTCC p.Asn976Ser	missense	N/A	Prot: ENSP00000454998.1 UniProt: Q12879-2

GRIN2A ENST00000330684.4

TSL:1MANE Select

HGVSc / HGVSpc.2926_2928delAATinsTCCp.Asn976Ser

Exon rankN/A

missense

Prot: ENSP00000332549.3UniProt: Q12879-1

GRIN2A ENST00000396573.6

TSL:1

HGVSc / HGVSpc.2926_2928delAATinsTCCp.Asn976Ser

Exon rankN/A

missense

Prot: ENSP00000379818.2UniProt: Q12879-1

GRIN2A ENST00000562109.5

TSL:1

HGVSc / HGVSpc.2926_2928delAATinsTCCp.Asn976Ser

Exon rankN/A

missense

Prot: ENSP00000454998.1UniProt: Q12879-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence