6-102055321-C-T

Variant names:

• chr6-102055321-C-T
• rs2227281
• NM_021956.5:c.2312-9C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021956.5(GRIK2):​c.2312-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,593,100 control chromosomes in the GnomAD database, including 81,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (6700 hom., cov: 32)
  • Exomes 𝑓: 0.32 (74903 hom.)
• Consequence: GRIK2 NM_021956.5 intron
• Scores: Splicing: ADA: 0.00001126
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.873
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-102055321-C-T is Benign according to our data. Variant chr6-102055321-C-T is described in ClinVar as Benign. ClinVar VariationId is 129174.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

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.2312-9C>T		intron	N/A	NP_068775.1
	GRIK2	NM_001166247.1		c.2312-9C>T		intron	N/A	NP_001159719.1
	GRIK2	NM_175768.3		c.2312-9C>T		intron	N/A	NP_786944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.2312-9C>T		intron	N/A	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.2312-9C>T		intron	N/A	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.2312-9C>T		intron	N/A	ENSP00000358134.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44813 AN: 151738 Hom.: 6705 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.306 AC: 75700 AN: 247068 AF XY: 0.305

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.320 AC: 460650 AN: 1441246 Hom.: 74903 Cov.: 27 AF XY: 0.318 AC XY: 227928 AN XY: 717150

African (AFR) AF: 0.227 AC: 7469 AN: 32944

American (AMR) AF: 0.309 AC: 13532 AN: 43846

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6796 AN: 25698

East Asian (EAS) AF: 0.344 AC: 13569 AN: 39500

South Asian (SAS) AF: 0.252 AC: 21432 AN: 85142

European-Finnish (FIN) AF: 0.331 AC: 17573 AN: 53138

Middle Eastern (MID) AF: 0.280 AC: 1587 AN: 5670

European-Non Finnish (NFE) AF: 0.329 AC: 360209 AN: 1095712

Other (OTH) AF: 0.310 AC: 18483 AN: 59596

GnomAD4 genome AF: 0.295 AC: 44814 AN: 151854 Hom.: 6700 Cov.: 32 AF XY: 0.295 AC XY: 21848 AN XY: 74168

African (AFR) AF: 0.228 AC: 9459 AN: 41442

American (AMR) AF: 0.299 AC: 4555 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 907 AN: 3468

East Asian (EAS) AF: 0.346 AC: 1771 AN: 5122

South Asian (SAS) AF: 0.263 AC: 1262 AN: 4806

European-Finnish (FIN) AF: 0.327 AC: 3442 AN: 10532

Middle Eastern (MID) AF: 0.290 AC: 84 AN: 290

European-Non Finnish (NFE) AF: 0.329 AC: 22360 AN: 67936

Other (OTH) AF: 0.290 AC: 611 AN: 2110

Alfa AF: 0.310 Hom.: 2477

Bravo AF: 0.293

Asia WGS AF: 0.272 AC: 947 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.52
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
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: rs2227281; hg19: chr6-102503196; COSMIC: COSV59720612;