16-9761937-G-A

Variant names:

• chr16-9761937-G-A
• rs1014531
• NM_001134407.3:c.*1212C>T

Variant summary

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

The NM_001134407.3(GRIN2A):​c.*1212C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 203,760 control chromosomes in the GnomAD database, including 12,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9038 hom., cov: 33)
  • Exomes 𝑓: 0.36 (3486 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.352
• Publications: 21 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=-0.81).
• BP6: Variant 16-9761937-G-A is Benign according to our data. Variant chr16-9761937-G-A is described in ClinVar as Benign. ClinVar VariationId is 321583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*1212C>T		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.*1212C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_001134407.3	ENSP00000332549.3
GRIN2A	ENST00000396573.6	c.*1212C>T		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000379818.2
GRIN2A	ENST00000674742.1	c.*1212C>T		3_prime_UTR_variant	Exon 12 of 12			ENSP00000502200.1
GRIN2A	ENST00000535259.6	c.*1418C>T		3_prime_UTR_variant	Exon 13 of 13	5		ENSP00000441572.3

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51269 AN: 152046 Hom.: 9035 Cov.: 33

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.358 AC: 18459 AN: 51596 Hom.: 3486 Cov.: 0 AF XY: 0.361 AC XY: 8677 AN XY: 24066

African (AFR) AF: 0.267 AC: 610 AN: 2284

American (AMR) AF: 0.301 AC: 445 AN: 1478

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1209 AN: 3286

East Asian (EAS) AF: 0.188 AC: 1511 AN: 8058

South Asian (SAS) AF: 0.247 AC: 109 AN: 442

European-Finnish (FIN) AF: 0.357 AC: 10 AN: 28

Middle Eastern (MID) AF: 0.354 AC: 114 AN: 322

European-Non Finnish (NFE) AF: 0.411 AC: 12884 AN: 31362

Other (OTH) AF: 0.361 AC: 1567 AN: 4336

GnomAD4 genome AF: 0.337 AC: 51295 AN: 152164 Hom.: 9038 Cov.: 33 AF XY: 0.327 AC XY: 24337 AN XY: 74400

African (AFR) AF: 0.268 AC: 11138 AN: 41498

American (AMR) AF: 0.316 AC: 4834 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1321 AN: 3468

East Asian (EAS) AF: 0.183 AC: 948 AN: 5180

South Asian (SAS) AF: 0.250 AC: 1203 AN: 4810

European-Finnish (FIN) AF: 0.286 AC: 3032 AN: 10598

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27647 AN: 67988

Other (OTH) AF: 0.343 AC: 725 AN: 2112

Alfa AF: 0.383 Hom.: 44985

Bravo AF: 0.337

Asia WGS AF: 0.231 AC: 806 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Landau-Kleffner syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.62
PhyloP100		0.35
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: rs1014531; hg19: chr16-9855794;