6-101799798-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_021956.5(GRIK2):c.1095+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,608,086 control chromosomes in the GnomAD database, including 39,052 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.26 (6998 hom., cov: 32)
  • Exomes 𝑓: 0.18 (32054 hom.)
• Consequence: GRIK2 NM_021956.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001427
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0140

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-101799798-T-C is Benign according to our data. Variant chr6-101799798-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129169.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-101799798-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK2	NM_021956.5	c.1095+7T>C		splice_region_variant, intron_variant		ENST00000369134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK2	ENST00000369134.9	c.1095+7T>C		splice_region_variant, intron_variant		5	NM_021956.5	P4

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39882 AN: 151744 Hom.: 6966 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.251 AC: 62874 AN: 250648 Hom.: 10973 AF XY: 0.246 AC XY: 33341 AN XY: 135452

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.695

Gnomad SAS exome AF: 0.361

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.180 AC: 262387 AN: 1456222 Hom.: 32054 Cov.: 29 AF XY: 0.183 AC XY: 132995 AN XY: 724850

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.263 AC: 39976 AN: 151864 Hom.: 6998 Cov.: 32 AF XY: 0.271 AC XY: 20082 AN XY: 74200

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.687

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.243

Alfa AF: 0.170 Hom.: 5819

Bravo AF: 0.270

Asia WGS AF: 0.514 AC: 1789 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.132

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.8
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.034
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: rs6922753; hg19: chr6-102247673; COSMIC: COSV59746950;