21-29553703-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000399907.6(GRIK1):c.2609C>T(p.Ala870Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.007 in 1,554,896 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A870S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 58 hom. )

Consequence

GRIK1
ENST00000399907.6 missense, splice_region

Scores

Splicing: ADA: 0.6846

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.93

Variant links:

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]

GRIK1 links:

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]

BACH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048614144).

BP6

Variant 21-29553703-G-A is Benign according to our data. Variant chr21-29553703-G-A is described in ClinVar as [Benign]. Clinvar id is 782668.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK1	NM_001330994.2 linkuse as main transcript	c.2607+1349C>T		intron_variant		ENST00000327783.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK1	ENST00000327783.9 linkuse as main transcript	c.2607+1349C>T		intron_variant		5	NM_001330994.2	A1

Frequencies

GnomAD3 genomes

AF:

0.00522

AC:

793

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00200

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00678

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00515

AC:

1103

AN:

214334

Hom.:

AF XY:

0.00544

AC XY:

638

AN XY:

117264

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.00200

Gnomad EAS exome

AF:

0.0000637

Gnomad SAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.00608

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00720

AC:

10099

AN:

1403002

Hom.:

Cov.:

AF XY:

0.00725

AC XY:

5056

AN XY:

697278

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00577

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0113

Gnomad4 FIN exome

AF:

0.00175

Gnomad4 NFE exome

AF:

0.00775

Gnomad4 OTH exome

AF:

0.00772

GnomAD4 genome

AF:

0.00522

AC:

793

AN:

151894

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

358

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.00200

Gnomad4 NFE

AF:

0.00678

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00569

Hom.:

Bravo

AF:

0.00585

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00249

AC:

ESP6500EA

AF:

0.00711

AC:

ExAC

AF:

0.00501

AC:

605

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

0.013

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.60

N;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.065

Sift

Benign

0.23

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.043

B;.

Vest4

0.27

MVP

0.75

MPC

0.21

ClinPred

0.012

GERP RS

4.5

Varity_R

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.68

dbscSNV1_RF

Benign

0.65

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over