16-9754612-T-TG

Variant names:

• chr16-9754612-T-TG
• rs59371229
• NM_001134407.3:c.*8536_*8537insC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001134407.3(GRIN2A):​c.*8536_*8537insC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 216,630 control chromosomes in the GnomAD database, including 25 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (3 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.762
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1784/152256) while in subpopulation AFR AF = 0.0402 (1671/41552). AF 95% confidence interval is 0.0386. There are 22 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*8536_*8537insC		3_prime_UTR_variant	Exon 13 of 13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.*8536_*8537insC		3_prime_UTR_variant	Exon 13 of 13	1	NM_001134407.3	ENSP00000332549.3
GRIN2A	ENST00000396573.6	c.*8536_*8537insC		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000379818.2

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1777 AN: 152138 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00245 AC: 158 AN: 64374 Hom.: 3 Cov.: 0 AF XY: 0.00201 AC XY: 60 AN XY: 29778

African (AFR) AF: 0.0387 AC: 115 AN: 2974

American (AMR) AF: 0.00715 AC: 14 AN: 1958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4042

East Asian (EAS) AF: 0.00 AC: 0 AN: 9344

South Asian (SAS) AF: 0.00 AC: 0 AN: 556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 384

European-Non Finnish (NFE) AF: 0.0000504 AC: 2 AN: 39644

Other (OTH) AF: 0.00497 AC: 27 AN: 5432

GnomAD4 genome AF: 0.0117 AC: 1784 AN: 152256 Hom.: 22 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74464

African (AFR) AF: 0.0402 AC: 1671 AN: 41552

American (AMR) AF: 0.00536 AC: 82 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68008

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.0102 Hom.: 8

Bravo AF: 0.0138

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.76

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: rs59371229; hg19: chr16-9848469;