5-178981680-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000843.4(GRM6):c.2611G>A(p.Glu871Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

GRM6
NM_000843.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2539224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4 linkuse as main transcript	c.2611G>A	p.Glu871Lys	missense_variant	11/11	ENST00000517717.3
ZNF454	XR_007058600.1 linkuse as main transcript	n.5644-8067C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3 linkuse as main transcript	c.2611G>A	p.Glu871Lys	missense_variant	11/11	5	NM_000843.4	P1
	ENST00000519491.1 linkuse as main transcript	n.305-8067C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250810

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135618

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000603

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 871 of the GRM6 protein (p.Glu871Lys). This variant is present in population databases (rs150479026, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GRM6-related conditions. ClinVar contains an entry for this variant (Variation ID: 854338). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRM6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.092

T;T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;.;.

M_CAP

Benign

0.032

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.30

N;N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.027

D;D;.

Sift4G

Benign

0.73

T;T;.

Polyphen

0.95

P;P;P

Vest4

0.22

MVP

0.82

MPC

0.12

ClinPred

0.73

GERP RS

4.6

Varity_R

0.24

gMVP

0.41

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