21-29553703-G-A

Position:

• chr21-29553703-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.93

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 -16 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_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIK1	NM_001330994.2	c.2607+1349C>T		intron_variant		ENST00000327783.9	NP_001317923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIK1	ENST00000327783.9	c.2607+1349C>T		intron_variant		5	NM_001330994.2	ENSP00000327687	A1

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 793 AN: 151774 Hom.: 5 Cov.: 32

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.: 7 AF XY: 0.00544 AC XY: 638 AN XY: 117264

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.: 58 Cov.: 26 AF XY: 0.00725 AC XY: 5056 AN XY: 697278

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.: 5 Cov.: 32 AF XY: 0.00482 AC XY: 358 AN XY: 74242

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.: 12

Bravo AF: 0.00585

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00249 AC: 9

ESP6500EA AF: 0.00711 AC: 58

ExAC AF: 0.00501 AC: 605

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.013
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N;N
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs363503; hg19: chr21-30926024; COSMIC: COSV105176458;