rs3213608

Positions:

• chr6-102035551-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021956.5(GRIK2):​c.2296G>A​(p.Val766Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,589,202 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: GRIK2 NM_021956.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.95

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 -18 ACMG points.

• PM1: In a topological_domain Extracellular (size 162) in uniprot entity GRIK2_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_021956.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.00972122).
• BP6: Variant 6-102035551-G-A is Benign according to our data. Variant chr6-102035551-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00279 (423/151370) while in subpopulation AMR AF= 0.024 (363/15118). AF 95% confidence interval is 0.022. There are 5 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK2	NM_021956.5	c.2296G>A	p.Val766Ile	missense_variant	15/17	ENST00000369134.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK2	ENST00000369134.9	c.2296G>A	p.Val766Ile	missense_variant	15/17	5	NM_021956.5	P4

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 422 AN: 151256 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00409

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000281

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00342 AC: 853 AN: 249648 Hom.: 14 AF XY: 0.00281 AC XY: 379 AN XY: 134962

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.0219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00338

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00101 AC: 1446 AN: 1437832 Hom.: 22 Cov.: 26 AF XY: 0.000931 AC XY: 667 AN XY: 716476

Gnomad4 AFR exome AF: 0.000305

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00561

Gnomad4 SAS exome AF: 0.0000468

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00279 AC: 423 AN: 151370 Hom.: 5 Cov.: 31 AF XY: 0.00316 AC XY: 234 AN XY: 73938

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00390

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000281

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.000792 Hom.: 0

Bravo AF: 0.00363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Intellectual disability, autosomal recessive 6;C5562006:Neurodevelopmental disorder with impaired language and ataxia and with or without seizures Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Benign	0.40
DEOGEN2	Benign	0.21	T;.;.;T;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.082
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
MetaRNN	Benign	0.0097	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.6	N;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.27	N;N;N;.;N;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T;.;D;.
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0060	B;B;B;.;.;.
Vest4		0.28
MVP		0.27
MPC		0.82
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs3213608; hg19: chr6-102483426; COSMIC: COSV59783951; COSMIC: COSV59783951;