rs367543140

chr16-9829650-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4 BP6_Moderate BS1 BS2

The NM_001134407.3(GRIN2A):c.1780C>T(p.Pro594Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000143 in 1,608,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P594P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GRIN2A NM_001134407.3 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 6.79

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.3432088).
• BP6: Variant 16-9829650-G-A is Benign according to our data. Variant chr16-9829650-G-A is described in ClinVar as [Benign]. Clinvar id is 98469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000329 (5/152106) while in subpopulation EAS AF= 0.000771 (4/5190). AF 95% confidence interval is 0.000263. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.1780C>T	p.Pro594Ser	missense_variant, splice_region_variant	9/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.1780C>T	p.Pro594Ser	missense_variant, splice_region_variant	9/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250734 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1456570 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 724958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

not provided Other:1

not provided, no classification provided

literature only

Psychiatry Genetics Yale University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.6	D;.;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.12	T;.;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.41
MutPred		0.30		Gain of glycosylation at P594 (P = 0.074);.;Gain of glycosylation at P594 (P = 0.074);Gain of glycosylation at P594 (P = 0.074);
MVP		0.64
MPC		2.6
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs367543140; hg19: chr16-9923507; COSMIC: COSV58026208;