6-101889856-A-G

Variant names:

• chr6-101889856-A-G
• rs1554281005
• NM_021956.5:c.1741A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_021956.5(GRIK2):​c.1741A>G​(p.Ile581Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,445,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GRIK2 NM_021956.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

GRIK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• intellectual disability, autosomal recessive 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neurodevelopmental disorder with impaired language and ataxia and with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021956.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.1741A>G	p.Ile581Val	missense	Exon 12 of 17	NP_068775.1
	GRIK2	NM_001166247.1		c.1741A>G	p.Ile581Val	missense	Exon 11 of 17	NP_001159719.1
	GRIK2	NM_175768.3		c.1741A>G	p.Ile581Val	missense	Exon 11 of 17	NP_786944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.1741A>G	p.Ile581Val	missense	Exon 12 of 17	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.1741A>G	p.Ile581Val	missense	Exon 14 of 19	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.1741A>G	p.Ile581Val	missense	Exon 11 of 17	ENSP00000358134.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1445944 Hom.: 0 Cov.: 28 AF XY: 0.0000125 AC XY: 9 AN XY: 720386

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1097630

Other (OTH) AF: 0.00 AC: 0 AN: 59888

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.12	N
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.58
Sift	Benign	0.49	T
Sift4G	Benign	0.76	T
Polyphen		0.93	P
Vest4		0.49
MutPred		0.45		Loss of sheet (P = 0.302)
MVP		0.80
MPC		2.0
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.38
Mutation Taster		=7/93	disease causing

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: rs1554281005; hg19: chr6-102337731;