21-29553607-A-G

Variant names:

• chr21-29553607-A-G
• rs363504
• ENST00000399907.6:c.2705T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000830.6(GRIK1):​c.2705T>C​(p.Leu902Ser) variant causes a missense change. The variant allele was found at a frequency of 0.055 in 1,608,156 control chromosomes in the GnomAD database, including 3,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.092 (986 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2670 hom.)
• Consequence: GRIK1 NM_000830.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22
• Publications: 22 publications found

Genes affected

GRIK1 (HGNC:4579): (glutamate ionotropic receptor kainate type subunit 1) 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 (CAG->CGG; Q->R) within the second transmembrane domain, which is thought to alter the properties of ion flow. Alternative splicing, resulting in transcript variants encoding different isoforms, has been noted for this gene. [provided by RefSeq, Jul 2008]

BACH1 (HGNC:935): (BTB domain and CNC homolog 1) This gene encodes a transcription factor that belongs to the cap'n'collar type of basic region leucine zipper factor family (CNC-bZip). The encoded protein contains broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) domains, which is atypical of CNC-bZip family members. These BTB/POZ domains facilitate protein-protein interactions and formation of homo- and/or hetero-oligomers. When this encoded protein forms a heterodimer with MafK, it functions as a repressor of Maf recognition element (MARE) and transcription is repressed. Multiple alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, May 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011906326).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000830.6. 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
	GRIK1	NM_001330994.2	MANE Select	c.2607+1445T>C		intron	N/A	NP_001317923.1	E7ENK3
	GRIK1	NM_000830.6		c.2705T>C	p.Leu902Ser	missense	Exon 17 of 17	NP_000821.1	P39086-1
	GRIK1	NM_001410706.1		c.2660T>C	p.Leu887Ser	missense	Exon 16 of 16	NP_001397635.1	E7EPZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK1	ENST00000399907.6	TSL:1	c.2705T>C	p.Leu902Ser	missense	Exon 17 of 17	ENSP00000382791.1	P39086-1
	GRIK1	ENST00000327783.9	TSL:5 MANE Select	c.2607+1445T>C		intron	N/A	ENSP00000327687.4	E7ENK3
	GRIK1	ENST00000389125.7	TSL:1	c.2562+1445T>C		intron	N/A	ENSP00000373777.3	P39086-2

Frequencies

GnomAD3 genomes AF: 0.0919 AC: 13920 AN: 151476 Hom.: 986 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0738

Gnomad EAS AF: 0.0779

Gnomad SAS AF: 0.0574

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0932

GnomAD2 exomes AF: 0.0667 AC: 16508 AN: 247482 AF XY: 0.0613

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.0794

Gnomad EAS exome AF: 0.0719

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0511 AC: 74469 AN: 1456562 Hom.: 2670 Cov.: 29 AF XY: 0.0504 AC XY: 36500 AN XY: 724724

African (AFR) AF: 0.191 AC: 6340 AN: 33196

American (AMR) AF: 0.131 AC: 5773 AN: 44076

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 2152 AN: 26016

East Asian (EAS) AF: 0.0728 AC: 2883 AN: 39590

South Asian (SAS) AF: 0.0574 AC: 4913 AN: 85534

European-Finnish (FIN) AF: 0.0233 AC: 1243 AN: 53256

Middle Eastern (MID) AF: 0.0874 AC: 502 AN: 5742

European-Non Finnish (NFE) AF: 0.0424 AC: 47065 AN: 1108982

Other (OTH) AF: 0.0598 AC: 3598 AN: 60170

GnomAD4 genome AF: 0.0920 AC: 13950 AN: 151594 Hom.: 986 Cov.: 32 AF XY: 0.0920 AC XY: 6812 AN XY: 74078

African (AFR) AF: 0.190 AC: 7833 AN: 41318

American (AMR) AF: 0.134 AC: 2048 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 256 AN: 3468

East Asian (EAS) AF: 0.0779 AC: 402 AN: 5160

South Asian (SAS) AF: 0.0574 AC: 275 AN: 4788

European-Finnish (FIN) AF: 0.0193 AC: 203 AN: 10526

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2704 AN: 67796

Other (OTH) AF: 0.0922 AC: 194 AN: 2104

Alfa AF: 0.0571 Hom.: 1602

Bravo AF: 0.104

TwinsUK AF: 0.0480 AC: 178

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.174 AC: 637

ESP6500EA AF: 0.0444 AC: 363

ExAC AF: 0.0660 AC: 7977

Asia WGS AF: 0.0700 AC: 244 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.094
Sift	Benign	0.052	T
Sift4G	Benign	0.58	T
Polyphen		0.26	B
Vest4		0.16
MPC		0.29
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.068
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs363504; hg19: chr21-30925928; COSMIC: COSV58725813;