Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000845.3(GRM8):c.693T>C(p.Gly231Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,954 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 42 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 43 hom. )

Consequence

GRM8
NM_000845.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.00800

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 7-127106530-A-G is Benign according to our data. Variant chr7-127106530-A-G is described in ClinVar as Benign. ClinVar VariationId is 776257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.008 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (2000/152266) while in subpopulation AFR AF = 0.0451 (1875/41544). AF 95% confidence interval is 0.0434. There are 42 homozygotes in GnomAd4. There are 939 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRM8	NM_000845.3	MANE Select	c.693T>C	p.Gly231Gly	synonymous	Exon 3 of 11	NP_000836.2
GRM8	NM_001371086.1		c.693T>C	p.Gly231Gly	synonymous	Exon 3 of 12	NP_001358015.1
GRM8	NM_001127323.1		c.693T>C	p.Gly231Gly	synonymous	Exon 3 of 11	NP_001120795.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRM8	ENST00000339582.7	TSL:5 MANE Select	c.693T>C	p.Gly231Gly	synonymous	Exon 3 of 11	ENSP00000344173.2
GRM8	ENST00000358373.8	TSL:1	c.693T>C	p.Gly231Gly	synonymous	Exon 3 of 11	ENSP00000351142.3
GRM8	ENST00000341617.7	TSL:1	n.693T>C		non_coding_transcript_exon	Exon 2 of 11	ENSP00000345747.3

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1999

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0452

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00570

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00324

AC:

813

AN:

251138

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.0443

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00137

AC:

2007

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

926

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0474

AC:

1588

AN:

33472

American (AMR)

AF:

0.00230

AC:

103

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000115

AC:

128

AN:

1111878

Other (OTH)

AF:

0.00280

AC:

169

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0131

AC:

2000

AN:

152266

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

939

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0451

AC:

1875

AN:

41544

American (AMR)

AF:

0.00569

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68018

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00754

Hom.:

Bravo

AF:

0.0148

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GRM8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.4

(source)

DANN

Benign

0.73

PhyloP100

-0.0080

PromoterAI

0.030

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs17866780

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over