16-9763190-G-A

Variant names:

• chr16-9763190-G-A
• rs568622613
• NM_001134407.3:c.4354C>T
• GRIN2A p.Arg1452Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP6_Moderate

The NM_001134407.3(GRIN2A):c.4354C>T (p.Arg1452Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000682 (AC=11) in the gnomAD database across 1,613,648 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. 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.R1452H: Likely_benign (ClinVar VariationId 573254, 1 star); p.R1452= (synonymous): Likely_benign (ClinVar VariationId 1397598, 1 star); p.R1452= (synonymous): Benign/Likely_benign (ClinVar VariationId 238192, 2 stars); p.R1452S: Uncertain_significance (ClinVar VariationId 520729, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Gliomas; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 6.41
• Publications: 1 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: Uncertain_significance. The variant received 0 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 = 0.00000488 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 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.4354C>T p.Arg1452Cys	missense	Exon 13 of 13	Prot: NP_001127879.1 UniProt:
	GRIN2A NM_000833.5		c.4354C>T p.Arg1452Cys	missense	Exon 14 of 14	Prot: NP_000824.1 UniProt:
	GRIN2A NM_001134408.2		c.*165C>T	3_prime_UTR	Exon 14 of 14	Prot: NP_001127880.1 UniProt:

GRIN2A NM_001134407.3

MANE Select

HGVSc / HGVSpc.4354C>Tp.Arg1452Cys

Exon rankExon 13 of 13

missense

Prot: NP_001127879.1UniProt: Q12879-1

GRIN2A NM_000833.5

HGVSc / HGVSpc.4354C>Tp.Arg1452Cys

Exon rankExon 14 of 14

missense

Prot: NP_000824.1UniProt: Q12879-1

GRIN2A NM_001134408.2

HGVSc / HGVSpc.*165C>T

Exon rankExon 14 of 14

3_prime_UTR

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.4354C>T p.Arg1452Cys	missense	Exon 13 of 13	Prot: ENSP00000332549.3 UniProt:
	GRIN2A ENST00000396573.6	TSL:1	c.4354C>T p.Arg1452Cys	missense	Exon 14 of 14	Prot: ENSP00000379818.2 UniProt:
	GRIN2A ENST00000562109.5	TSL:1	c.*165C>T	3_prime_UTR	Exon 14 of 14	Prot: ENSP00000454998.1 UniProt:

GRIN2A ENST00000330684.4

TSL:1MANE Select

HGVSc / HGVSpc.4354C>Tp.Arg1452Cys

Exon rankExon 13 of 13

missense

Prot: ENSP00000332549.3UniProt: Q12879-1

GRIN2A ENST00000396573.6

TSL:1

HGVSc / HGVSpc.4354C>Tp.Arg1452Cys

Exon rankExon 14 of 14

missense

Prot: ENSP00000379818.2UniProt: Q12879-1

GRIN2A ENST00000562109.5

TSL:1

HGVSc / HGVSpc.*165C>T

Exon rankExon 14 of 14

3_prime_UTR

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: 0.0000197	AC:3	Hom:0	AN:152102	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251140	Cov:
GnomAD4 exome	AF: 0.00000547	AC:8	Hom:0	AN:1461428	Cov:31
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152220	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000939	AC:2	Hom:0	AN:21310	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000291	3	103052	0.0000109	2	184150

Showing 1 cohortAllele 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, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability (1)
-	-	1	Landau-Kleffner syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Benign	0.10
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Uncertain	2.4	M
PhyloP100	Uncertain	6.4
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Varity_R	N/A	0.42
VESM-3B	Benign	-6.4

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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: rs568622613;

hg19: chr16-9857047;

COSMIC: COSV58025217;

COSMIC: COSV58025217;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar