chr21-29553607-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK1	NM_001330994.2	c.2607+1445T>C		intron_variant	Intron 16 of 17	ENST00000327783.9	NP_001317923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK1	ENST00000327783.9	c.2607+1445T>C		intron_variant	Intron 16 of 17	5	NM_001330994.2	ENSP00000327687.4

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

GnomAD3 exomes AF: 0.0667 AC: 16508 AN: 247482 Hom.: 853 AF XY: 0.0613 AC XY: 8242 AN XY: 134372

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 SAS exome AF: 0.0558

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

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.0827

Gnomad4 EAS exome AF: 0.0728

Gnomad4 SAS exome AF: 0.0574

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.0424

Gnomad4 OTH exome AF: 0.0598

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

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0738

Gnomad4 EAS AF: 0.0779

Gnomad4 SAS AF: 0.0574

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0922

Alfa AF: 0.0520 Hom.: 609

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 v4.3

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;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.094
Sift	Benign	0.052	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.26	B;.
Vest4		0.16
MPC		0.29
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.068

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

Publications

LitVar

Other links and lift over

dbSNP: rs363504; hg19: chr21-30925928; COSMIC: COSV58725813;