Genetic Variant GRM6:c.2125-1093G>A (chr5-178984314-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000843.4(GRM6):c.2125-1093G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.934 in 151,904 control chromosomes in the GnomAD database, including 66,353 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.93 ( 66353 hom., cov: 33)

Consequence

GRM6
NM_000843.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.845

Publications

4 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 links:

ENSG00000254035 (HGNC:):

ENSG00000254035 links:

ZNF454 (HGNC:21200): (zinc finger protein 454) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF454 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM6	NM_000843.4 link	c.2125-1093G>A		intron_variant	Intron 9 of 10	ENST00000517717.3	NP_000834.2	O15303
ZNF454	XR_007058600.1 link	n.5644-5433C>T		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3 link	c.2125-1093G>A		intron_variant	Intron 9 of 10	5	NM_000843.4	ENSP00000430767.1		O15303

Frequencies

GnomAD3 genomes

AF:

0.934

AC:

141734

AN:

151784

Hom.:

66307

Cov.:

show subpopulations

Gnomad AFR

AF:

0.888

Gnomad AMI

AF:

0.962

Gnomad AMR

AF:

0.931

Gnomad ASJ

AF:

0.938

Gnomad EAS

AF:

0.851

Gnomad SAS

AF:

0.914

Gnomad FIN

AF:

0.959

Gnomad MID

AF:

0.940

Gnomad NFE

AF:

0.965

Gnomad OTH

AF:

0.937

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.934

AC:

141838

AN:

151904

Hom.:

66353

Cov.:

AF XY:

0.932

AC XY:

69195

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.888

AC:

36842

AN:

41498

American (AMR)

AF:

0.931

AC:

14208

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.938

AC:

3253

AN:

3468

East Asian (EAS)

AF:

0.851

AC:

4373

AN:

5140

South Asian (SAS)

AF:

0.914

AC:

4406

AN:

4818

European-Finnish (FIN)

AF:

0.959

AC:

10117

AN:

10552

Middle Eastern (MID)

AF:

0.935

AC:

275

AN:

294

European-Non Finnish (NFE)

AF:

0.965

AC:

65519

AN:

67862

Other (OTH)

AF:

0.936

AC:

1979

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

474

948

1423

1897

2371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.951

Hom.:

90961

Bravo

AF:

0.932

Asia WGS

AF:

0.895

AC:

3116

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.84

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over