rs769194

chr7-127243176-G-C

Variant summary

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

The NM_000845.3(GRM8):c.29C>G(p.Ser10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,611,230 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 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.

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: GRM8 NM_000845.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.44

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010201514).
• BP6: Variant 7-127243176-G-C is Benign according to our data. Variant chr7-127243176-G-C is described in ClinVar as [Benign]. Clinvar id is 769732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM8	NM_000845.3	c.29C>G	p.Ser10Cys	missense_variant	2/11	ENST00000339582.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM8	ENST00000339582.7	c.29C>G	p.Ser10Cys	missense_variant	2/11	5	NM_000845.3	P1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00227 AC: 563 AN: 247916 Hom.: 7 AF XY: 0.00168 AC XY: 225 AN XY: 134196

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000474 AC: 691 AN: 1458922 Hom.: 6 Cov.: 31 AF XY: 0.000380 AC XY: 276 AN XY: 725834

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.00178

ExAC AF: 0.00159 AC: 193

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GRM8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.068
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	21
Dann	Benign	0.70
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;.;T;.
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.90	L;L;.;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.87	N;N;N;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Benign	0.066	T;T;.;.
Polyphen		0.83	P;P;.;.
Vest4		0.27
MVP		0.65
MPC		0.19
ClinPred		0.084	T
GERP RS		6.2
Varity_R		0.12
gMVP		0.40

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: rs769194; hg19: chr7-126883230;