rs62638197

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PP3_StrongPP5_Very_Strong

The NM_000843.4(GRM6):c.137C>T(p.Pro46Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,280,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000582705: Functional studies of the P46L variant demonstrated a transport defect with intracellular retention of the receptor (Zeitz et al., 2007" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P46P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000094 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

GRM6
NM_000843.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 7.35

Publications

7 publications found

Variant links:

Genes affected

GRM6 (HGNC:4598): (glutamate metabotropic receptor 6) 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. Mutations in this gene result in congenital stationary night blindness type 1B. [provided by RefSeq, May 2018]

GRM6 Gene-Disease associations (from GenCC):

congenital stationary night blindness 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
GRM6-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GRM6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000582705: Functional studies of the P46L variant demonstrated a transport defect with intracellular retention of the receptor (Zeitz et al., 2007; Beqollari et al., 2009).; SCV001401018: Experimental studies have shown that this missense change affects GRM6 function (PMID: 17405131, 19666700).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 5-178994808-G-A is Pathogenic according to our data. Variant chr5-178994808-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000843.4. 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
	GRM6	NM_000843.4	MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 2 of 11	NP_000834.2	O15303

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRM6	ENST00000517717.3	TSL:5 MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 2 of 11	ENSP00000430767.1	O15303
GRM6	ENST00000231188.9	TSL:2	c.137C>T	p.Pro46Leu	missense	Exon 1 of 10	ENSP00000231188.5	O15303
GRM6	ENST00000650031.1		c.137C>T	p.Pro46Leu	missense	Exon 3 of 12	ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes

AF:

0.0000937

AC:

AN:

149464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000730

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000835

AC:

AN:

23960

AF XY:

0.0000675

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000217

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

183

AN:

1130906

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

549874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22806

American (AMR)

AF:

0.00

AC:

AN:

11980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15310

East Asian (EAS)

AF:

0.00

AC:

AN:

23848

South Asian (SAS)

AF:

0.00

AC:

AN:

39878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3014

European-Non Finnish (NFE)

AF:

0.000187

AC:

177

AN:

945622

Other (OTH)

AF:

0.000135

AC:

AN:

44322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000936

AC:

AN:

149572

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

72994

show subpopulations

African (AFR)

AF:

0.0000727

AC:

AN:

41238

American (AMR)

AF:

0.00

AC:

AN:

15018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

67104

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.0000680

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital stationary night blindness (1)

Congenital stationary night blindness 1B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.3

PhyloP100

7.3

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.95

Vest4

0.90

MutPred

0.86

Gain of catalytic residue at P46 (P = 0.0246)

MVP

0.86

MPC

2.3

ClinPred

0.96

GERP RS

3.2

PromoterAI

0.029

Neutral

(source)

Varity_R

0.52

gMVP

0.66

Mutation Taster

=10/90

disease causing (ClinVar)

(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.

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

Computational scores

Splicing

Publications

Other links and lift over