rs2299459

Variant names:

• chr7-126555314-C-A
• rs2299459
• NM_000845.3:c.1495-21427G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-126555314-C-A
• chr7-126555314-C-G

Variant summary

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

The NM_000845.3(GRM8):​c.1495-21427G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 152,146 control chromosomes in the GnomAD database, including 44,233 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44233 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• Publications: 1 publications found

Genes affected

GRM8 (HGNC:4600): (glutamate metabotropic receptor 8) L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000845.3. 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
	GRM8	NM_000845.3	MANE Select	c.1495-21427G>T		intron	N/A	NP_000836.2	O00222-1
	GRM8	NM_001371086.1		c.1495-21427G>T		intron	N/A	NP_001358015.1	A0A9L9PYG5
	GRM8	NM_001127323.1		c.1495-21427G>T		intron	N/A	NP_001120795.1	O00222-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	ENST00000339582.7	TSL:5 MANE Select	c.1495-21427G>T		intron	N/A	ENSP00000344173.2	O00222-1
	GRM8	ENST00000358373.8	TSL:1	c.1495-21427G>T		intron	N/A	ENSP00000351142.3	O00222-2
	GRM8	ENST00000341617.7	TSL:1	n.*60-21427G>T		intron	N/A	ENSP00000345747.3	O00222-3

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115377 AN: 152028 Hom.: 44215 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.936

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.759

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.759 AC: 115441 AN: 152146 Hom.: 44233 Cov.: 32 AF XY: 0.762 AC XY: 56706 AN XY: 74378

African (AFR) AF: 0.678 AC: 28144 AN: 41484

American (AMR) AF: 0.707 AC: 10810 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2800 AN: 3472

East Asian (EAS) AF: 0.936 AC: 4838 AN: 5168

South Asian (SAS) AF: 0.772 AC: 3720 AN: 4816

European-Finnish (FIN) AF: 0.846 AC: 8961 AN: 10596

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53654 AN: 68004

Other (OTH) AF: 0.760 AC: 1609 AN: 2116

Alfa AF: 0.769 Hom.: 7337

Bravo AF: 0.744

Asia WGS AF: 0.833 AC: 2898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.37
DANN	Benign	0.48
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs2299459; hg19: chr7-126195368;