NM_021956.5:c.281A>C

Variant names:

• chr6-101622114-A-C
• NM_021956.5:c.281A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021956.5(GRIK2):​c.281A>C​(p.Lys94Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K94R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIK2 NM_021956.5 missense, splice_region
• Scores: Splicing: ADA: 0.5246
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31
• 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: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• intellectual disability, autosomal recessive 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.281A>C	p.Lys94Thr	missense splice_region	Exon 3 of 17	NP_068775.1	Q13002-1
	GRIK2	NM_001166247.1		c.281A>C	p.Lys94Thr	missense splice_region	Exon 2 of 17	NP_001159719.1	Q8IY40
	GRIK2	NM_175768.3		c.281A>C	p.Lys94Thr	missense splice_region	Exon 2 of 17	NP_786944.1	Q8IY40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.281A>C	p.Lys94Thr	missense splice_region	Exon 3 of 17	ENSP00000358130.6	Q13002-1
	GRIK2	ENST00000421544.6	TSL:1	c.281A>C	p.Lys94Thr	missense splice_region	Exon 5 of 19	ENSP00000397026.1	Q13002-1
	GRIK2	ENST00000369138.5	TSL:1	c.281A>C	p.Lys94Thr	missense splice_region	Exon 2 of 17	ENSP00000358134.1	Q13002-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.55
Sift	Benign	0.036	D
Sift4G	Benign	0.29	T
Polyphen		0.025	B
Vest4		0.73
MutPred		0.55		Loss of ubiquitination at K94 (P = 0.0218)
MVP		0.92
MPC		1.1
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.78
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.52
dbscSNV1_RF	Benign	0.53
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

hg19: chr6-102069989;