NM_021956.5:c.*1228T>C

Variant names:

• chr6-102069739-T-C
• rs28383483
• NM_021956.5:c.*1228T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_021956.5(GRIK2):​c.*1228T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 152,148 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GRIK2 NM_021956.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1736/152148) while in subpopulation NFE AF = 0.0177 (1202/67960). AF 95% confidence interval is 0.0169. There are 15 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK2	NM_021956.5	c.*1228T>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000369134.9	NP_068775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK2	ENST00000369134.9	c.*1228T>C		3_prime_UTR_variant	Exon 17 of 17	5	NM_021956.5	ENSP00000358130.6

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1737 AN: 152030 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0167

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0114 AC: 1736 AN: 152148 Hom.: 15 Cov.: 32 AF XY: 0.0108 AC XY: 800 AN XY: 74378

African (AFR) AF: 0.00318 AC: 132 AN: 41562

American (AMR) AF: 0.0168 AC: 256 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1202 AN: 67960

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.0120

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		-0.069
Mutation Taster		=100/0	polymorphism

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: rs28383483; hg19: chr6-102517614;