chr5-178991554-C-A

Position:

chr5-178991554-C-A

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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=0.015617073).

BP6

Variant 5-178991554-C-A is Benign according to our data. Variant chr5-178991554-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 99657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178991554-C-A is described in Lovd as [Likely_benign]. Variant chr5-178991554-C-A is described in Lovd as [Pathogenic].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM6	NM_000843.4 linkuse as main transcript	c.727G>T	p.Val243Phe	missense_variant	4/11	ENST00000517717.3	NP_000834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GRM6	ENST00000517717.3 linkuse as main transcript	c.727G>T	p.Val243Phe	missense_variant	4/11	5	NM_000843.4	ENSP00000430767	P1
GRM6	ENST00000231188.9 linkuse as main transcript	c.727G>T	p.Val243Phe	missense_variant	3/10	2		ENSP00000231188	P1
GRM6	ENST00000650031.1 linkuse as main transcript	c.727G>T	p.Val243Phe	missense_variant	5/12			ENSP00000497110	P1

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

GnomAD3 exomes

AF:

0.00502

AC:

1261

AN:

251300

Hom.:

AF XY:

0.00568

AC XY:

772

AN XY:

135838

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 SAS exome

AF:

0.0128

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

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.0377

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0134

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00253

Gnomad4 OTH exome

AF:

0.00565

GnomAD4 genome

AF:

0.00317

AC:

482

AN:

152070

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.0421

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00274

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00459

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

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GRM6: BS1, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -

Congenital stationary night blindness 1B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

GRM6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

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

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

MutationTaster

Benign

1.0

D;D

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

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

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