5-178994769-T-G

Position:

chr5-178994769-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000843.4(GRM6):c.176A>C(p.Gln59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,369,858 control chromosomes in the GnomAD database, including 240,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q59Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.57 ( 24597 hom., cov: 34)

Exomes 𝑓: 0.59 ( 215565 hom. )

Consequence

GRM6
NM_000843.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.195

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.1140935E-5).

BP6

Variant 5-178994769-T-G is Benign according to our data. Variant chr5-178994769-T-G is described in ClinVar as [Benign]. Clinvar id is 93438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178994769-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4 linkuse as main transcript	c.176A>C	p.Gln59Pro	missense_variant	2/11	ENST00000517717.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GRM6	ENST00000517717.3 linkuse as main transcript	c.176A>C	p.Gln59Pro	missense_variant	2/11	5	NM_000843.4	P1
GRM6	ENST00000231188.9 linkuse as main transcript	c.176A>C	p.Gln59Pro	missense_variant	1/10	2		P1
GRM6	ENST00000650031.1 linkuse as main transcript	c.176A>C	p.Gln59Pro	missense_variant	3/12			P1

Frequencies

GnomAD3 genomes

AF:

0.571

AC:

85484

AN:

149760

Hom.:

24568

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.347

Gnomad AMR

AF:

0.562

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.575

Gnomad SAS

AF:

0.500

Gnomad FIN

AF:

0.638

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.599

Gnomad OTH

AF:

0.533

GnomAD3 exomes

AF:

0.550

AC:

37270

AN:

67784

Hom.:

10477

AF XY:

0.539

AC XY:

21289

AN XY:

39532

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.584

Gnomad ASJ exome

AF:

0.503

Gnomad EAS exome

AF:

0.546

Gnomad SAS exome

AF:

0.463

Gnomad FIN exome

AF:

0.627

Gnomad NFE exome

AF:

0.584

Gnomad OTH exome

AF:

0.552

GnomAD4 exome

AF:

0.591

AC:

720965

AN:

1219992

Hom.:

215565

Cov.:

AF XY:

0.586

AC XY:

351108

AN XY:

599334

show subpopulations

Gnomad4 AFR exome

AF:

0.528

Gnomad4 AMR exome

AF:

0.573

Gnomad4 ASJ exome

AF:

0.495

Gnomad4 EAS exome

AF:

0.545

Gnomad4 SAS exome

AF:

0.450

Gnomad4 FIN exome

AF:

0.626

Gnomad4 NFE exome

AF:

0.605

Gnomad4 OTH exome

AF:

0.574

GnomAD4 genome

AF:

0.571

AC:

85561

AN:

149866

Hom.:

24597

Cov.:

AF XY:

0.572

AC XY:

41803

AN XY:

73122

show subpopulations

Gnomad4 AFR

AF:

0.533

Gnomad4 AMR

AF:

0.563

Gnomad4 ASJ

AF:

0.510

Gnomad4 EAS

AF:

0.574

Gnomad4 SAS

AF:

0.501

Gnomad4 FIN

AF:

0.638

Gnomad4 NFE

AF:

0.599

Gnomad4 OTH

AF:

0.537

Alfa

AF:

0.575

Hom.:

10825

Bravo

AF:

0.567

ESP6500AA

AF:

0.606

AC:

1561

ESP6500EA

AF:

0.652

AC:

3170

ExAC

AF:

0.439

AC:

17229

Asia WGS

AF:

0.554

AC:

1767

AN:

3188

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Congenital stationary night blindness 1B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.4

DANN

Benign

0.72

DEOGEN2

Benign

0.080

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.47

T;.;.

MetaRNN

Benign

0.000021

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.81

N;N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.52

N;N;.

REVEL

Benign

0.14

Sift

Benign

0.92

T;T;.

Sift4G

Benign

0.57

T;T;.

Polyphen

0.0

B;B;B

Vest4

0.060

MPC

1.5

ClinPred

0.0032

GERP RS

-2.4

Varity_R

0.11

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over