chr16-9938172-G-A

Variant names:

• chr16-9938172-G-A
• rs747214620
• NM_001134407.3:c.794C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000833.5(GRIN2A):​c.794C>T​(p.Thr265Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T265T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GRIN2A NM_000833.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.65
• Publications: 5 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-9938172-G-A is Benign according to our data. Variant chr16-9938172-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 577489.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000833.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	NM_001134407.3	MANE Select	c.794C>T	p.Thr265Met	missense	Exon 3 of 13	NP_001127879.1
	GRIN2A	NM_000833.5		c.794C>T	p.Thr265Met	missense	Exon 4 of 14	NP_000824.1
	GRIN2A	NM_001134408.2		c.794C>T	p.Thr265Met	missense	Exon 3 of 14	NP_001127880.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.794C>T	p.Thr265Met	missense	Exon 3 of 13	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.794C>T	p.Thr265Met	missense	Exon 4 of 14	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.794C>T	p.Thr265Met	missense	Exon 3 of 14	ENSP00000454998.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250962 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	0.0039	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.0	L
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.46
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.44		Loss of catalytic residue at T265 (P = 0.053)
MVP		0.66
MPC		1.4
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.60
Mutation Taster		=80/20	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: rs747214620; hg19: chr16-10032029; COSMIC: COSV58050698;