7-126532764-GATATATATATATATATATATATATATATATATATATATATAT-GATATATATATATATATATATATATATATAT

Variant names:

• chr7-126532764-GATATATATATAT-G
• rs521
• NM_000845.3:c.2430+176_2430+187delATATATATATAT

Variant summary

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

The NM_000845.3(GRM8):​c.2430+176_2430+187delATATATATATAT 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 0.0043 (4 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 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	NM_000845.3	MANE Select	c.2430+176_2430+187delATATATATATAT		intron	N/A	NP_000836.2
	GRM8	NM_001371086.1		c.2430+176_2430+187delATATATATATAT		intron	N/A	NP_001358015.1
	GRM8	NM_001127323.1		c.2430+176_2430+187delATATATATATAT		intron	N/A	NP_001120795.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	ENST00000339582.7	TSL:5 MANE Select	c.2430+176_2430+187delATATATATATAT		intron	N/A	ENSP00000344173.2
	GRM8	ENST00000358373.8	TSL:1	c.2430+176_2430+187delATATATATATAT		intron	N/A	ENSP00000351142.3
	GRM8	ENST00000341617.7	TSL:1	n.*995+176_*995+187delATATATATATAT		intron	N/A	ENSP00000345747.3

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 475 AN: 110866 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00583

Gnomad AMR AF: 0.00219

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00369

Gnomad SAS AF: 0.000941

Gnomad FIN AF: 0.000433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00456

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

GnomAD4 genome AF: 0.00429 AC: 476 AN: 110892 Hom.: 4 Cov.: 0 AF XY: 0.00415 AC XY: 217 AN XY: 52262

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0106 AC: 321 AN: 30188

American (AMR) AF: 0.00219 AC: 21 AN: 9600

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 13 AN: 2822

East Asian (EAS) AF: 0.00370 AC: 14 AN: 3784

South Asian (SAS) AF: 0.000945 AC: 3 AN: 3176

European-Finnish (FIN) AF: 0.000433 AC: 2 AN: 4614

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

European-Non Finnish (NFE) AF: 0.00168 AC: 91 AN: 54250

Other (OTH) AF: 0.00453 AC: 7 AN: 1546

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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;