5-178981834-C-T

Variant names:

• chr5-178981834-C-T
• rs2071249
• NM_000843.4:c.2457G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000843.4(GRM6):​c.2457G>A​(p.Thr819Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,612,124 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (561 hom.)
• Consequence: GRM6 NM_000843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 8 publications found

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]

ENSG00000254035 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-178981834-C-T is Benign according to our data. Variant chr5-178981834-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000843.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	NM_000843.4	MANE Select	c.2457G>A	p.Thr819Thr	synonymous	Exon 11 of 11	NP_000834.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	ENST00000517717.3	TSL:5 MANE Select	c.2457G>A	p.Thr819Thr	synonymous	Exon 11 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.2457G>A	p.Thr819Thr	synonymous	Exon 10 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.2457G>A	p.Thr819Thr	synonymous	Exon 12 of 12	ENSP00000497110.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1535 AN: 152182 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0172 AC: 4302 AN: 249850 AF XY: 0.0160

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.00856

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00695 AC: 10143 AN: 1459824 Hom.: 561 Cov.: 29 AF XY: 0.00702 AC XY: 5102 AN XY: 726412

African (AFR) AF: 0.00126 AC: 42 AN: 33442

American (AMR) AF: 0.0277 AC: 1238 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26120

East Asian (EAS) AF: 0.157 AC: 6248 AN: 39674

South Asian (SAS) AF: 0.0112 AC: 967 AN: 86186

European-Finnish (FIN) AF: 0.00802 AC: 428 AN: 53372

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.000490 AC: 544 AN: 1110244

Other (OTH) AF: 0.0104 AC: 627 AN: 60312

GnomAD4 genome AF: 0.0101 AC: 1537 AN: 152300 Hom.: 73 Cov.: 32 AF XY: 0.0119 AC XY: 889 AN XY: 74464

African (AFR) AF: 0.00135 AC: 56 AN: 41566

American (AMR) AF: 0.0317 AC: 486 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.144 AC: 744 AN: 5176

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4824

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68022

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00364 Hom.: 8

Bravo AF: 0.0113

Asia WGS AF: 0.0650 AC: 224 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.0
DANN	Benign	0.87
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2071249; hg19: chr5-178408835; COSMIC: COSV51442866; COSMIC: COSV51442866;