5-178981543-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000843.4(GRM6):c.*114C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 809,564 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (175 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1086 hom.)
• Consequence: GRM6 NM_000843.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.71

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-178981543-G-C is Benign according to our data. Variant chr5-178981543-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1706847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4	c.*114C>G		3_prime_UTR_variant	11/11	ENST00000517717.3
ZNF454	XR_007058600.1	n.5644-8204G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3	c.*114C>G		3_prime_UTR_variant	11/11	5	NM_000843.4	P1
	ENST00000519491.1	n.305-8204G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5392 AN: 151954 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.00674

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0572

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0852

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0451

GnomAD4 exome AF: 0.0454 AC: 29844 AN: 657492 Hom.: 1086 Cov.: 9 AF XY: 0.0483 AC XY: 16507 AN XY: 341806

Gnomad4 AFR exome AF: 0.00777

Gnomad4 AMR exome AF: 0.0429

Gnomad4 ASJ exome AF: 0.0569

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.0912

Gnomad4 FIN exome AF: 0.0362

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.0355 AC: 5392 AN: 152072 Hom.: 175 Cov.: 32 AF XY: 0.0376 AC XY: 2794 AN XY: 74310

Gnomad4 AFR AF: 0.00669

Gnomad4 AMR AF: 0.0572

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.0851

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0340

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0362 Hom.: 17

Bravo AF: 0.0333

Asia WGS AF: 0.0930 AC: 323 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2020

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.58
Dann	Benign	0.43

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

Other links and lift over

dbSNP: rs17078852; hg19: chr5-178408544;