rs180799513

chr6-102055322-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021956.5(GRIK2):c.2312-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 1,603,348 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (143 hom.)
• Consequence: GRIK2 NM_021956.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002136
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.653

Genes affected

GRIK2 (HGNC:4580): (glutamate ionotropic receptor kainate type subunit 2) Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. Mutations in this gene have been associated with autosomal recessive cognitive disability. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-102055322-T-G is Benign according to our data. Variant chr6-102055322-T-G is described in ClinVar as [Benign]. Clinvar id is 129173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-102055322-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK2	NM_021956.5	c.2312-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000369134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK2	ENST00000369134.9	c.2312-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_021956.5	P4

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152070 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.0119 AC: 2967 AN: 248478 Hom.: 104 AF XY: 0.00992 AC XY: 1333 AN XY: 134364

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.00235

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00505

Gnomad FIN exome AF: 0.00154

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00920

GnomAD4 exome AF: 0.00462 AC: 6698 AN: 1451160 Hom.: 143 Cov.: 29 AF XY: 0.00440 AC XY: 3180 AN XY: 722142

Gnomad4 AFR exome AF: 0.000874

Gnomad4 AMR exome AF: 0.0655

Gnomad4 ASJ exome AF: 0.00317

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00547

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.00455

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152188 Hom.: 6 Cov.: 32 AF XY: 0.00479 AC XY: 356 AN XY: 74382

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00326

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00362 Hom.: 2

Bravo AF: 0.00867

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00357

EpiControl AF: 0.00316

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	3.4
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.070
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: rs180799513; hg19: chr6-102503197;