7-126580415-C-A

Position:

• chr7-126580415-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000845.3(GRM8):​c.1494+28947G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,002 control chromosomes in the GnomAD database, including 8,133 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 0.31 (8133 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM8	NM_000845.3	c.1494+28947G>T		intron_variant		ENST00000339582.7	NP_000836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM8	ENST00000339582.7	c.1494+28947G>T		intron_variant		5	NM_000845.3	ENSP00000344173	P1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46944 AN: 151886 Hom.: 8134 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.309 AC: 46947 AN: 152002 Hom.: 8133 Cov.: 32 AF XY: 0.309 AC XY: 22983 AN XY: 74280

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.317

Alfa AF: 0.352 Hom.: 1644

Bravo AF: 0.295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.69

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: rs2299472; hg19: chr7-126220469;