rs769198

Positions:

• chr7-126609392-G-A
• chr7-126609392-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_000845.3(GRM8):​c.1464C>T​(p.Ile488=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,276 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: GRM8 NM_000845.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.408

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 7-126609392-G-A is Benign according to our data. Variant chr7-126609392-G-A is described in ClinVar as [Benign]. Clinvar id is 782707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM8	NM_000845.3	c.1464C>T	p.Ile488=	synonymous_variant	8/11	ENST00000339582.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM8	ENST00000339582.7	c.1464C>T	p.Ile488=	synonymous_variant	8/11	5	NM_000845.3	P1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00356 AC: 894 AN: 251368 Hom.: 2 AF XY: 0.00327 AC XY: 444 AN XY: 135846

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00906

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00218 AC: 3191 AN: 1460984 Hom.: 12 Cov.: 29 AF XY: 0.00209 AC XY: 1521 AN XY: 726828

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00888

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.00306 AC XY: 228 AN XY: 74472

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00237

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.0
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs769198; hg19: chr7-126249446;