chr6-116793041-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_148963.4(GPRC6A):​c.1882G>A​(p.Gly628Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GPRC6A
NM_148963.4 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.89
Variant links:
Genes affected
GPRC6A (HGNC:18510): (G protein-coupled receptor class C group 6 member A) Members of family C of the G protein-coupled receptor (GPCR) superfamily, such as GPRC6A, are characterized by an evolutionarily conserved amino acid-sensing motif linked to an intramembranous 7-transmembrane loop region. Several members of GPCR family C, including GPRC6A, also have a long N-terminal domain (summary by Pi et al., 2005 [PubMed 16199532]).[supplied by OMIM, Nov 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GPRC6ANM_148963.4 linkuse as main transcriptc.1882G>A p.Gly628Arg missense_variant 6/6 ENST00000310357.8 NP_683766.2
GPRC6ANM_001286355.1 linkuse as main transcriptc.1669G>A p.Gly557Arg missense_variant 5/5 NP_001273284.1
GPRC6ANM_001286354.1 linkuse as main transcriptc.1357G>A p.Gly453Arg missense_variant 6/6 NP_001273283.1
GPRC6AXM_017010475.2 linkuse as main transcriptc.1741G>A p.Gly581Arg missense_variant 7/7 XP_016865964.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GPRC6AENST00000310357.8 linkuse as main transcriptc.1882G>A p.Gly628Arg missense_variant 6/61 NM_148963.4 ENSP00000309493 P1Q5T6X5-1
GPRC6AENST00000368549.7 linkuse as main transcriptc.1669G>A p.Gly557Arg missense_variant 5/51 ENSP00000357537 Q5T6X5-3
GPRC6AENST00000530250.1 linkuse as main transcriptc.1357G>A p.Gly453Arg missense_variant 6/61 ENSP00000433465 Q5T6X5-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250724
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135474
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461634
Hom.:
0
Cov.:
37
AF XY:
0.0000330
AC XY:
24
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 2021The c.1882G>A (p.G628R) alteration is located in exon 6 (coding exon 6) of the GPRC6A gene. This alteration results from a G to A substitution at nucleotide position 1882, causing the glycine (G) at amino acid position 628 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.68
D;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
3.4
M;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.0070
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.86
MutPred
0.66
Loss of glycosylation at S627 (P = 0.0408);.;.;
MVP
0.91
MPC
0.32
ClinPred
0.94
D
GERP RS
5.1
Varity_R
0.25
gMVP
0.77

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374630779; hg19: chr6-117114204; COSMIC: COSV100114325; API