5-178989881-C-T

Variant names:

• chr5-178989881-C-T
• rs762724
• NM_000843.4:c.1013-476G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000843.4(GRM6):​c.1013-476G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 233,814 control chromosomes in the GnomAD database, including 32,592 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 0.52 (20807 hom., cov: 32)
  • Exomes 𝑓: 0.52 (11785 hom.)
• Consequence: GRM6 NM_000843.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.649
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM6	NM_000843.4	c.1013-476G>A		intron_variant	Intron 5 of 10	ENST00000517717.3	NP_000834.2
ZNF454	XR_007058600.1	n.5778C>T		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3	c.1013-476G>A		intron_variant	Intron 5 of 10	5	NM_000843.4	ENSP00000430767.1
ENSG00000254035	ENST00000519491.1	n.439C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
GRM6	ENST00000231188.9	c.1013-476G>A		intron_variant	Intron 4 of 9	2		ENSP00000231188.5
GRM6	ENST00000650031.1	c.1013-476G>A		intron_variant	Intron 6 of 11			ENSP00000497110.1

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79027 AN: 151906 Hom.: 20780 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.486

GnomAD4 exome AF: 0.524 AC: 42837 AN: 81788 Hom.: 11785 Cov.: 0 AF XY: 0.512 AC XY: 21624 AN XY: 42230

African (AFR) AF: 0.449 AC: 1332 AN: 2964

American (AMR) AF: 0.551 AC: 2266 AN: 4110

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 918 AN: 2050

East Asian (EAS) AF: 0.572 AC: 2477 AN: 4330

South Asian (SAS) AF: 0.433 AC: 4520 AN: 10442

European-Finnish (FIN) AF: 0.534 AC: 1776 AN: 3324

Middle Eastern (MID) AF: 0.389 AC: 126 AN: 324

European-Non Finnish (NFE) AF: 0.544 AC: 27125 AN: 49878

Other (OTH) AF: 0.526 AC: 2297 AN: 4366

GnomAD4 genome AF: 0.520 AC: 79102 AN: 152026 Hom.: 20807 Cov.: 32 AF XY: 0.521 AC XY: 38734 AN XY: 74312

African (AFR) AF: 0.463 AC: 19219 AN: 41470

American (AMR) AF: 0.537 AC: 8208 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1657 AN: 3472

East Asian (EAS) AF: 0.567 AC: 2928 AN: 5160

South Asian (SAS) AF: 0.480 AC: 2316 AN: 4828

European-Finnish (FIN) AF: 0.561 AC: 5911 AN: 10540

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.550 AC: 37411 AN: 67966

Other (OTH) AF: 0.491 AC: 1035 AN: 2106

Alfa AF: 0.539 Hom.: 7802

Bravo AF: 0.519

Asia WGS AF: 0.556 AC: 1934 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.56
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs762724; hg19: chr5-178416882; COSMIC: COSV51445987; COSMIC: COSV51445987;