7-126532764-GATATATATATATATATATATATATATATATATATATATATAT-GATATATATATAT

Variant names:

• chr7-126532764-GATATATATATATATATATATATATATATAT-G
• rs521
• NM_000845.3:c.2430+158_2430+187delATATATATATATATATATATATATATATAT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000845.3(GRM8):​c.2430+158_2430+187delATATATATATATATATATATATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0016 (5 hom., cov: 0)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98
• Publications: 3 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]

ENSG00000287568 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 5 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.2430+158_2430+187delATATATATATATATATATATATATATATAT		intron	N/A	NP_000836.2
	GRM8	NM_001371086.1		c.2430+158_2430+187delATATATATATATATATATATATATATATAT		intron	N/A	NP_001358015.1
	GRM8	NM_001127323.1		c.2430+158_2430+187delATATATATATATATATATATATATATATAT		intron	N/A	NP_001120795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	ENST00000339582.7	TSL:5 MANE Select	c.2430+158_2430+187delATATATATATATATATATATATATATATAT		intron	N/A	ENSP00000344173.2
	GRM8	ENST00000358373.8	TSL:1	c.2430+158_2430+187delATATATATATATATATATATATATATATAT		intron	N/A	ENSP00000351142.3
	GRM8	ENST00000341617.7	TSL:1	n.*995+158_*995+187delATATATATATATATATATATATATATATAT		intron	N/A	ENSP00000345747.3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 182 AN: 110904 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.0522

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00142

Gnomad EAS AF: 0.00105

Gnomad SAS AF: 0.000940

Gnomad FIN AF: 0.00305

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00130

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

GnomAD4 genome AF: 0.00163 AC: 181 AN: 110930 Hom.: 5 Cov.: 0 AF XY: 0.00195 AC XY: 102 AN XY: 52270

African (AFR) AF: 0.00109 AC: 33 AN: 30252

American (AMR) AF: 0.00281 AC: 27 AN: 9592

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 4 AN: 2820

East Asian (EAS) AF: 0.00106 AC: 4 AN: 3782

South Asian (SAS) AF: 0.000629 AC: 2 AN: 3178

European-Finnish (FIN) AF: 0.00305 AC: 14 AN: 4592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00109 AC: 59 AN: 54254

Other (OTH) AF: 0.00130 AC: 2 AN: 1544

Alfa AF: 0.00 Hom.: 267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs521; hg19: chr7-126172818;