16-9764617-T-C

Variant names:

• chr16-9764617-T-C
• rs886039239
• NM_001134407.3:c.2927A>G
• GRIN2A p.Asn976Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_Strong

The NM_001134407.3(GRIN2A):c.2927A>G (p.Asn976Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000547 (AC=8) in the gnomAD database across 1,461,818 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000262. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N976K: Uncertain_significance (ClinVar VariationId 4750046, 1 star) 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)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 4.54
• Publications: 8 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: 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000262 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GRIN2A NM_001134407.3	MANE Select	c.2927A>G p.Asn976Ser	missense	Exon 13 of 13	Prot: NP_001127879.1 UniProt:
	GRIN2A NM_000833.5		c.2927A>G p.Asn976Ser	missense	Exon 14 of 14	Prot: NP_000824.1 UniProt:
	GRIN2A NM_001134408.2		c.2927A>G p.Asn976Ser	missense	Exon 13 of 14	Prot: NP_001127880.1 UniProt:

GRIN2A NM_001134407.3

MANE Select

HGVSc / HGVSpc.2927A>Gp.Asn976Ser

Exon rankExon 13 of 13

missense

Prot: NP_001127879.1UniProt: Q12879-1

GRIN2A NM_000833.5

HGVSc / HGVSpc.2927A>Gp.Asn976Ser

Exon rankExon 14 of 14

missense

Prot: NP_000824.1UniProt: Q12879-1

GRIN2A NM_001134408.2

HGVSc / HGVSpc.2927A>Gp.Asn976Ser

Exon rankExon 13 of 14

missense

Prot: NP_001127880.1UniProt: Q12879-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GRIN2A ENST00000330684.4	TSL:1MANE Select	c.2927A>G p.Asn976Ser	missense	Exon 13 of 13	Prot: ENSP00000332549.3 UniProt:
	GRIN2A ENST00000396573.6	TSL:1	c.2927A>G p.Asn976Ser	missense	Exon 14 of 14	Prot: ENSP00000379818.2 UniProt:
	GRIN2A ENST00000562109.5	TSL:1	c.2927A>G p.Asn976Ser	missense	Exon 13 of 14	Prot: ENSP00000454998.1 UniProt:

GRIN2A ENST00000330684.4

TSL:1MANE Select

HGVSc / HGVSpc.2927A>Gp.Asn976Ser

Exon rankExon 13 of 13

missense

Prot: ENSP00000332549.3UniProt: Q12879-1

GRIN2A ENST00000396573.6

TSL:1

HGVSc / HGVSpc.2927A>Gp.Asn976Ser

Exon rankExon 14 of 14

missense

Prot: ENSP00000379818.2UniProt: Q12879-1

GRIN2A ENST00000562109.5

TSL:1

HGVSc / HGVSpc.2927A>Gp.Asn976Ser

Exon rankExon 13 of 14

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251302	Cov:
GnomAD4 exome	AF: 0.00000547	AC:8	Hom:0	AN:1461818	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888
SCHEMA(Schizophrenia)	0.00	0	56394	0.00000900	1	111096

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Landau-Kleffner syndrome (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
FuncVEP CTI	Benign	0.0064
GPN-Star LLR	N/A	-2.7
GPN-Star score	N/A	2.7
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	3/97	disease causing
MutationAssessor	Uncertain	2.8	M
PhyloP100	Uncertain	4.5
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Benign	0.089	T
Sift4G	Benign	0.077	T
Varity_R	N/A	0.10
VESM-3B	Benign	-2.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs886039239;

hg19: chr16-9858474;

COSMIC: COSV105221266;

COSMIC: COSV105221266;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar