rs17078894

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000843.4(GRM6):c.727G>T(p.Val243Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,612,786 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V243L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 40 hom. )

Consequence

GRM6
NM_000843.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.841

Publications

13 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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015617073).

BP6

Variant 5-178991554-C-A is Benign according to our data. Variant chr5-178991554-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00317 (482/152070) while in subpopulation SAS AF = 0.0145 (70/4814). AF 95% confidence interval is 0.0118. There are 7 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM6	NM_000843.4 link	c.727G>T	p.Val243Phe	missense_variant	Exon 4 of 11	ENST00000517717.3	NP_000834.2	O15303

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRM6	ENST00000517717.3 link	c.727G>T	p.Val243Phe	missense_variant	Exon 4 of 11	5	NM_000843.4	ENSP00000430767.1	O15303
GRM6	ENST00000231188.9 link	c.727G>T	p.Val243Phe	missense_variant	Exon 3 of 10	2		ENSP00000231188.5	O15303
GRM6	ENST00000650031.1 link	c.727G>T	p.Val243Phe	missense_variant	Exon 5 of 12			ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00502

AC:

1261

AN:

251300

AF XY:

0.00568

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0380

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00323

Gnomad OTH exome

AF:

0.00848

GnomAD4 exome

AF:

0.00376

AC:

5492

AN:

1460716

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

3050

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33456

American (AMR)

AF:

0.00165

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0377

AC:

986

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0134

AC:

1159

AN:

86232

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00253

AC:

2814

AN:

1111010

Other (OTH)

AF:

0.00565

AC:

341

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00317

AC:

482

AN:

152070

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41488

American (AMR)

AF:

0.00281

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

146

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.0145

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00274

AC:

186

AN:

67966

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00381

Hom.:

Bravo

AF:

0.00294

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00463

AC:

562

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GRM6: BS1, BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not specified

Benign:2

Jan 25, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 26, 2015

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital stationary night blindness 1B

Benign:1

Apr 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GRM6-related disorder

Benign:1

May 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;.;.

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.4

M;M;M

PhyloP100

0.84

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;D;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0040

D;D;.

Polyphen

0.98

D;D;D

Vest4

0.77

MVP

0.88

MPC

0.45

ClinPred

0.035

GERP RS

5.2

Varity_R

0.62

gMVP

0.55

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over