5-178994926-C-T

Position:

chr5-178994926-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000843.4(GRM6):c.19G>A(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,189,594 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0078 ( 45 hom. )

Consequence

GRM6
NM_000843.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.52

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:

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=0.0041314065).

BP6

Variant 5-178994926-C-T is Benign according to our data. Variant chr5-178994926-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178994926-C-T is described in Lovd as [Benign]. Variant chr5-178994926-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00617 (935/151488) while in subpopulation NFE AF= 0.00915 (619/67644). AF 95% confidence interval is 0.00855. There are 6 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM6	NM_000843.4 linkuse as main transcript	c.19G>A	p.Ala7Thr	missense_variant	2/11	ENST00000517717.3	NP_000834.2	O15303

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRM6	ENST00000517717.3 linkuse as main transcript	c.19G>A	p.Ala7Thr	missense_variant	2/11	5	NM_000843.4	ENSP00000430767.1	O15303
GRM6	ENST00000231188.9 linkuse as main transcript	c.19G>A	p.Ala7Thr	missense_variant	1/10	2		ENSP00000231188.5	O15303
GRM6	ENST00000650031.1 linkuse as main transcript	c.19G>A	p.Ala7Thr	missense_variant	3/12			ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes

AF:

0.00619

AC:

937

AN:

151380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00710

Gnomad ASJ

AF:

0.0200

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00470

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00915

Gnomad OTH

AF:

0.00816

GnomAD3 exomes

AF:

0.0102

AC:

AN:

3836

Hom.:

AF XY:

0.0109

AC XY:

AN XY:

2294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.0194

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00262

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00862

GnomAD4 exome

AF:

0.00783

AC:

8125

AN:

1038106

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

3835

AN XY:

493400

show subpopulations

Gnomad4 AFR exome

AF:

0.000672

Gnomad4 AMR exome

AF:

0.00749

Gnomad4 ASJ exome

AF:

0.0174

Gnomad4 EAS exome

AF:

0.0000466

Gnomad4 SAS exome

AF:

0.00366

Gnomad4 FIN exome

AF:

0.00400

Gnomad4 NFE exome

AF:

0.00825

Gnomad4 OTH exome

AF:

0.00726

GnomAD4 genome

AF:

0.00617

AC:

935

AN:

151488

Hom.:

Cov.:

AF XY:

0.00593

AC XY:

439

AN XY:

73992

show subpopulations

Gnomad4 AFR

AF:

0.00145

Gnomad4 AMR

AF:

0.00709

Gnomad4 ASJ

AF:

0.0200

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00470

Gnomad4 NFE

AF:

0.00915

Gnomad4 OTH

AF:

0.00807

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00605

ExAC

AF:

0.00156

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GRM6: PP2, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.27

DANN

Benign

0.97

DEOGEN2

Benign

0.089

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.33

T;.;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.11

N;N;.

REVEL

Benign

0.16

Sift

Benign

0.60

T;T;.

Sift4G

Benign

0.66

T;T;.

Polyphen

0.0010

B;B;B

Vest4

0.070

MVP

0.33

MPC

1.2

ClinPred

0.0073

GERP RS

-1.6

Varity_R

0.023

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