7-126532764-GATATATATATATATATATATATATATATATATATATATATAT-GATATATATATATATATATATATATATATATATATATATATATAT

Variant names:

• chr7-126532764-G-GAT
• rs521
• NM_000845.3:c.2430+186_2430+187dupAT

Variant summary

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

The NM_000845.3(GRM8):​c.2430+186_2430+187dupAT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0057 (13 hom., cov: 0)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• 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 13 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+186_2430+187dupAT		intron	N/A	NP_000836.2
	GRM8	NM_001371086.1		c.2430+186_2430+187dupAT		intron	N/A	NP_001358015.1
	GRM8	NM_001127323.1		c.2430+186_2430+187dupAT		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+187_2430+188insAT		intron	N/A	ENSP00000344173.2
	GRM8	ENST00000358373.8	TSL:1	c.2430+187_2430+188insAT		intron	N/A	ENSP00000351142.3
	GRM8	ENST00000341617.7	TSL:1	n.*995+187_*995+188insAT		intron	N/A	ENSP00000345747.3

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 634 AN: 110476 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00145

Gnomad AMR AF: 0.00325

Gnomad ASJ AF: 0.00853

Gnomad EAS AF: 0.00344

Gnomad SAS AF: 0.00409

Gnomad FIN AF: 0.000651

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00458

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

GnomAD4 genome AF: 0.00574 AC: 634 AN: 110502 Hom.: 13 Cov.: 0 AF XY: 0.00505 AC XY: 263 AN XY: 52070

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

African (AFR) AF: 0.00381 AC: 115 AN: 30196

American (AMR) AF: 0.00325 AC: 31 AN: 9532

Ashkenazi Jewish (ASJ) AF: 0.00853 AC: 24 AN: 2812

East Asian (EAS) AF: 0.00346 AC: 13 AN: 3762

South Asian (SAS) AF: 0.00410 AC: 13 AN: 3170

European-Finnish (FIN) AF: 0.000651 AC: 3 AN: 4606

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

European-Non Finnish (NFE) AF: 0.00791 AC: 427 AN: 53968

Other (OTH) AF: 0.00455 AC: 7 AN: 1540

⚠️ 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		-0.34

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;