7-126446381-A-AG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000845.3(GRM8):c.2431-10_2431-9insC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,564,058 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: GRM8 NM_000845.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0410

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 Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 7-126446381-A-AG is Benign according to our data. Variant chr7-126446381-A-AG is described in ClinVar as [Benign]. Clinvar id is 3044373.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM8	NM_000845.3	c.2431-10_2431-9insC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000339582.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM8	ENST00000339582.7	c.2431-10_2431-9insC		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000845.3	P1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 154 AN: 149726 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00337

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000722

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.00150 AC: 340 AN: 227346 Hom.: 0 AF XY: 0.00194 AC XY: 240 AN XY: 123654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000735

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.0000592

Gnomad SAS exome AF: 0.00727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.000996 AC: 1408 AN: 1414222 Hom.: 2 Cov.: 25 AF XY: 0.00124 AC XY: 871 AN XY: 702966

Gnomad4 AFR exome AF: 0.0000641

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00773

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000499

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome AF: 0.00103 AC: 155 AN: 149836 Hom.: 1 Cov.: 32 AF XY: 0.000929 AC XY: 68 AN XY: 73190

Gnomad4 AFR AF: 0.000226

Gnomad4 AMR AF: 0.00337

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00625

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000723

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000370 Hom.: 1

Bravo AF: 0.00137

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRM8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

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). -

Computational scores

Source: dbNSFP v4.3

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: rs568174461; hg19: chr7-126086435;