rs4701014

Variant names:

• chr5-178988981-A-G
• rs4701014
• NM_000843.4:c.1308T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-178988981-A-G
• chr5-178988981-A-C
• chr5-178988981-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000843.4(GRM6):​c.1308T>C​(p.Thr436Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,614,002 control chromosomes in the GnomAD database, including 802,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73899 hom., cov: 33)
  • Exomes 𝑓: 1.0 (728772 hom.)
• Consequence: GRM6 NM_000843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.68
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 5-178988981-A-G is Benign according to our data. Variant chr5-178988981-A-G is described in ClinVar as Benign. ClinVar VariationId is 198105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.1308T>C	p.Thr436Thr	synonymous	Exon 7 of 11	NP_000834.2	O15303

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	ENST00000517717.3	TSL:5 MANE Select	c.1308T>C	p.Thr436Thr	synonymous	Exon 7 of 11	ENSP00000430767.1	O15303
	GRM6	ENST00000231188.9	TSL:2	c.1308T>C	p.Thr436Thr	synonymous	Exon 6 of 10	ENSP00000231188.5	O15303
	GRM6	ENST00000650031.1		c.1308T>C	p.Thr436Thr	synonymous	Exon 8 of 12	ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149841 AN: 152130 Hom.: 73843 Cov.: 33

Gnomad AFR AF: 0.947

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.996 AC: 248874 AN: 249816 AF XY: 0.997

Gnomad AFR exome AF: 0.947

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1459591 AN: 1461754 Hom.: 728772 Cov.: 54 AF XY: 0.999 AC XY: 726213 AN XY: 727162

African (AFR) AF: 0.946 AC: 31660 AN: 33476

American (AMR) AF: 0.998 AC: 44624 AN: 44716

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26131 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86212 AN: 86232

European-Finnish (FIN) AF: 1.00 AC: 53398 AN: 53398

Middle Eastern (MID) AF: 0.998 AC: 5714 AN: 5726

European-Non Finnish (NFE) AF: 1.00 AC: 1111945 AN: 1111988

Other (OTH) AF: 0.997 AC: 60209 AN: 60386

GnomAD4 genome AF: 0.985 AC: 149957 AN: 152248 Hom.: 73899 Cov.: 33 AF XY: 0.986 AC XY: 73420 AN XY: 74430

African (AFR) AF: 0.947 AC: 39362 AN: 41556

American (AMR) AF: 0.996 AC: 15242 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5132 AN: 5132

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68005 AN: 68012

Other (OTH) AF: 0.989 AC: 2087 AN: 2110

Alfa AF: 0.991 Hom.: 43693

Bravo AF: 0.983

Asia WGS AF: 0.997 AC: 3467 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Congenital stationary night blindness 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.021
DANN	Benign	0.32
PhyloP100		-2.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4701014; hg19: chr5-178415982; COSMIC: COSV99179673; COSMIC: COSV99179673;