rs186727716

Variant names:

• chr6-101859329-T-A
• rs186727716
• NM_021956.5:c.1360T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-101859329-T-A
• chr6-101859329-T-C

Variant summary

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

The NM_021956.5(GRIK2):​c.1360T>A​(p.Tyr454Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,632 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y454H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRIK2 NM_021956.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK2	NM_021956.5	c.1360T>A	p.Tyr454Asn	missense_variant	Exon 11 of 17	ENST00000369134.9	NP_068775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK2	ENST00000369134.9	c.1360T>A	p.Tyr454Asn	missense_variant	Exon 11 of 17	5	NM_021956.5	ENSP00000358130.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453632 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 723766

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104784

Other (OTH) AF: 0.00 AC: 0 AN: 60146

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T;.;.;T;.;T;T;.
Eigen	Benign	0.036
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.3	L;L;L;.;.;.;.;.
PhyloP100		4.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D;D;D;.;.;.;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.16	T;T;T;.;.;.;D;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T
Polyphen		0.54	P;B;B;.;.;.;.;.
Vest4		0.62
MutPred		0.43		Gain of disorder (P = 0.021);Gain of disorder (P = 0.021);Gain of disorder (P = 0.021);.;.;.;.;.;
MVP		0.94
MPC		2.1
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.39
gMVP		0.69
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186727716; hg19: chr6-102307204;