chr6-101686292-C-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4BP6BS2
The NM_021956.5(GRIK2):c.890C>G(p.Ser297Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,996 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 2 hom. )
Consequence
GRIK2
NM_021956.5 missense
NM_021956.5 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.57
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.31675082).
BP6
Variant 6-101686292-C-G is Benign according to our data. Variant chr6-101686292-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435364.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIK2 | NM_021956.5 | c.890C>G | p.Ser297Trp | missense_variant | 7/17 | ENST00000369134.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIK2 | ENST00000369134.9 | c.890C>G | p.Ser297Trp | missense_variant | 7/17 | 5 | NM_021956.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00102 AC: 155AN: 151832Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000824 AC: 207AN: 251138Hom.: 0 AF XY: 0.000818 AC XY: 111AN XY: 135716
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GnomAD4 exome AF: 0.00145 AC: 2125AN: 1461046Hom.: 2 Cov.: 30 AF XY: 0.00139 AC XY: 1009AN XY: 726860
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GnomAD4 genome AF: 0.00102 AC: 155AN: 151950Hom.: 0 Cov.: 32 AF XY: 0.000875 AC XY: 65AN XY: 74272
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 24, 2016 | - - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
GRIK2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;.;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
D;D;D;.;.;.;.
Vest4
MVP
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ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at