Genetic Variant GRM8:p.Lys872Thr (chr7-126446188-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000845.3(GRM8):c.2615A>C(p.Lys872Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K872R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

GRM8
NM_000845.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.97

Publications

0 publications found

Variant links:

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]

GRM8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRM8	NM_000845.3	MANE Select	c.2615A>C	p.Lys872Thr	missense	Exon 10 of 11	NP_000836.2	O00222-1
GRM8	NM_001371086.1		c.2615A>C	p.Lys872Thr	missense	Exon 10 of 12	NP_001358015.1	A0A9L9PYG5
GRM8	NM_001127323.1		c.2615A>C	p.Lys872Thr	missense	Exon 10 of 11	NP_001120795.1	O00222-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRM8	ENST00000339582.7	TSL:5 MANE Select	c.2615A>C	p.Lys872Thr	missense	Exon 10 of 11	ENSP00000344173.2	O00222-1
GRM8	ENST00000358373.8	TSL:1	c.2615A>C	p.Lys872Thr	missense	Exon 10 of 11	ENSP00000351142.3	O00222-2
GRM8	ENST00000341617.7	TSL:1	n.*1180A>C		non_coding_transcript_exon	Exon 10 of 11	ENSP00000345747.3	O00222-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

0.096

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.2

PhyloP100

5.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.68

Sift

Benign

0.039

Sift4G

Benign

0.14

Polyphen

0.28

Vest4

0.46

MutPred

0.32

Loss of methylation at K872 (P = 0.0172)

MVP

0.61

MPC

0.30

ClinPred

0.90

GERP RS

4.7

Varity_R

0.18

gMVP

0.59

Mutation Taster

=47/53

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over