7-126609392-G-A

Variant names:

• chr7-126609392-G-A
• rs769198
• NM_000845.3:c.1464C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000845.3(GRM8):​c.1464C>T​(p.Ile488Ile) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.408
• Publications: 5 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 -15 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 VariationId is 782707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 12 gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	NM_000845.3	MANE Select	c.1464C>T	p.Ile488Ile	synonymous	Exon 8 of 11	NP_000836.2
	GRM8	NM_001371086.1		c.1464C>T	p.Ile488Ile	synonymous	Exon 8 of 12	NP_001358015.1
	GRM8	NM_001127323.1		c.1464C>T	p.Ile488Ile	synonymous	Exon 8 of 11	NP_001120795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	ENST00000339582.7	TSL:5 MANE Select	c.1464C>T	p.Ile488Ile	synonymous	Exon 8 of 11	ENSP00000344173.2
	GRM8	ENST00000358373.8	TSL:1	c.1464C>T	p.Ile488Ile	synonymous	Exon 8 of 11	ENSP00000351142.3
	GRM8	ENST00000341617.7	TSL:1	n.*29C>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000345747.3

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

GnomAD2 exomes AF: 0.00356 AC: 894 AN: 251368 AF XY: 0.00327

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33470

American (AMR) AF: 0.00888 AC: 397 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26128

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39672

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86218

European-Finnish (FIN) AF: 0.0101 AC: 537 AN: 53412

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00179 AC: 1993 AN: 1111260

Other (OTH) AF: 0.00254 AC: 153 AN: 60350

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

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.00405 AC: 62 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.0
DANN	Benign	0.79
PhyloP100		-0.41
Mutation Taster		=93/7	polymorphism

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: rs769198; hg19: chr7-126249446; COSMIC: COSV108179648;