7-126770047-C-G

Variant names:

• chr7-126770047-C-G
• rs2234947
• NM_000845.3:c.1175G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000845.3(GRM8):​c.1175G>C​(p.Arg392Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRM8 NM_000845.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM8	NM_000845.3	c.1175G>C	p.Arg392Pro	missense_variant	Exon 7 of 11	ENST00000339582.7	NP_000836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM8	ENST00000339582.7	c.1175G>C	p.Arg392Pro	missense_variant	Exon 7 of 11	5	NM_000845.3	ENSP00000344173.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		1.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.073	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.63	P;D
Vest4		0.77
MutPred		0.55		Loss of MoRF binding (P = 0.028);Loss of MoRF binding (P = 0.028);
MVP		0.56
MPC		0.30
ClinPred		0.54	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.85
Mutation Taster		=60/40	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: rs2234947; hg19: chr7-126410101;