rs376029542

Variant names:

• chr16-9822267-G-A
• rs376029542
• NM_001134407.3:c.2165C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS1

The NM_000833.5(GRIN2A):​c.2165C>T​(p.Thr722Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T722T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: GRIN2A NM_000833.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.56
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000833.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.23339662).
• BP6: Variant 16-9822267-G-A is Benign according to our data. Variant chr16-9822267-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287546.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00023 (35/152260) while in subpopulation AFR AF = 0.00077 (32/41548). AF 95% confidence interval is 0.00056. There are 0 homozygotes in GnomAd4. There are 12 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_000833.5. 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.2165C>T	p.Thr722Met	missense	Exon 10 of 13	NP_001127879.1
	GRIN2A	NM_000833.5		c.2165C>T	p.Thr722Met	missense	Exon 11 of 14	NP_000824.1
	GRIN2A	NM_001134408.2		c.2165C>T	p.Thr722Met	missense	Exon 10 of 14	NP_001127880.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.2165C>T	p.Thr722Met	missense	Exon 10 of 13	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.2165C>T	p.Thr722Met	missense	Exon 11 of 14	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.2165C>T	p.Thr722Met	missense	Exon 10 of 14	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251176 AF XY: 0.0000884

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727070

African (AFR) AF: 0.000478 AC: 16 AN: 33456

American (AMR) AF: 0.000224 AC: 10 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111728

Other (OTH) AF: 0.0000828 AC: 5 AN: 60386

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74440

African (AFR) AF: 0.000770 AC: 32 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Landau-Kleffner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Benign	0.13	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.25
MVP		0.69
MPC		2.5
ClinPred		0.078	T
GERP RS		5.7
Varity_R		0.39
gMVP		0.66
Mutation Taster		=45/55	disease causing

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: rs376029542; hg19: chr16-9916124; COSMIC: COSV58045743;