21-29555248-C-T

Variant names:

• chr21-29555248-C-T
• rs1171746300
• NM_001330994.2:c.2411G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001330994.2(GRIK1):​c.2411G>A​(p.Gly804Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIK1 NM_001330994.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02
• Publications: 0 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]

LOC124905006 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330994.2. 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.2411G>A	p.Gly804Glu	missense	Exon 16 of 18	NP_001317923.1	E7ENK3
	GRIK1	NM_001330993.2		c.2366G>A	p.Gly789Glu	missense	Exon 15 of 17	NP_001317922.1	E7EPY9
	GRIK1	NM_001320616.2		c.2411G>A	p.Gly804Glu	missense	Exon 16 of 17	NP_001307545.1	E9PD61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK1	ENST00000327783.9	TSL:5 MANE Select	c.2411G>A	p.Gly804Glu	missense	Exon 16 of 18	ENSP00000327687.4	E7ENK3
	GRIK1	ENST00000399907.6	TSL:1	c.2411G>A	p.Gly804Glu	missense	Exon 16 of 17	ENSP00000382791.1	P39086-1
	GRIK1	ENST00000389125.7	TSL:1	c.2366G>A	p.Gly789Glu	missense	Exon 15 of 16	ENSP00000373777.3	P39086-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.87	P
Vest4		0.79
MutPred		0.81		Gain of solvent accessibility (P = 0.0638)
MVP		0.79
MPC		0.59
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.95
Mutation Taster		=9/91	disease causing

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: rs1171746300; hg19: chr21-30927569;