16-9768699-G-T

Variant names:

• chr16-9768699-G-T
• rs11866328
• NM_001134407.3:c.2595+152C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000833.5(GRIN2A):​c.2595+152C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 753,224 control chromosomes in the GnomAD database, including 54,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11361 hom., cov: 33)
  • Exomes 𝑓: 0.37 (42760 hom.)
• Consequence: GRIN2A NM_000833.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.601
• Publications: 37 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-9768699-G-T is Benign according to our data. Variant chr16-9768699-G-T is described in ClinVar as Benign. ClinVar VariationId is 681804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

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.2595+152C>A		intron	N/A	NP_001127879.1
	GRIN2A	NM_000833.5		c.2595+152C>A		intron	N/A	NP_000824.1
	GRIN2A	NM_001134408.2		c.2595+152C>A		intron	N/A	NP_001127880.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.2595+152C>A		intron	N/A	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.2595+152C>A		intron	N/A	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.2595+152C>A		intron	N/A	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57901 AN: 151928 Hom.: 11356 Cov.: 33

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.380

GnomAD4 exome AF: 0.368 AC: 221270 AN: 601178 Hom.: 42760 AF XY: 0.365 AC XY: 119366 AN XY: 327310

African (AFR) AF: 0.399 AC: 6722 AN: 16840

American (AMR) AF: 0.287 AC: 11902 AN: 41432

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 8023 AN: 20064

East Asian (EAS) AF: 0.186 AC: 6641 AN: 35652

South Asian (SAS) AF: 0.260 AC: 17610 AN: 67826

European-Finnish (FIN) AF: 0.307 AC: 12278 AN: 40010

Middle Eastern (MID) AF: 0.348 AC: 1306 AN: 3754

European-Non Finnish (NFE) AF: 0.421 AC: 144602 AN: 343568

Other (OTH) AF: 0.380 AC: 12186 AN: 32032

GnomAD4 genome AF: 0.381 AC: 57940 AN: 152046 Hom.: 11361 Cov.: 33 AF XY: 0.369 AC XY: 27446 AN XY: 74322

African (AFR) AF: 0.394 AC: 16334 AN: 41462

American (AMR) AF: 0.337 AC: 5143 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3470

East Asian (EAS) AF: 0.180 AC: 932 AN: 5174

South Asian (SAS) AF: 0.258 AC: 1242 AN: 4808

European-Finnish (FIN) AF: 0.294 AC: 3104 AN: 10574

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28520 AN: 67972

Other (OTH) AF: 0.381 AC: 804 AN: 2108

Alfa AF: 0.405 Hom.: 38265

Bravo AF: 0.386

Asia WGS AF: 0.244 AC: 853 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.48
DANN	Benign	0.74
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

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: rs11866328; hg19: chr16-9862556; COSMIC: COSV58033400;