rs2274911

Positions:

• chr6-116809541-G-A
• chr6-116809541-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_148963.4(GPRC6A):​c.271C>T​(p.Pro91Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,611,776 control chromosomes in the GnomAD database, including 429,790 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.74 (41663 hom., cov: 32)
  • Exomes 𝑓: 0.73 (388127 hom.)
• Consequence: GPRC6A NM_148963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.315

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.667584E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRC6A	NM_148963.4	c.271C>T	p.Pro91Ser	missense_variant	2/6	ENST00000310357.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRC6A	ENST00000310357.8	c.271C>T	p.Pro91Ser	missense_variant	2/6	1	NM_148963.4	P1
GPRC6A	ENST00000368549.7	c.271C>T	p.Pro91Ser	missense_variant	2/5	1
GPRC6A	ENST00000530250.1	c.271C>T	p.Pro91Ser	missense_variant	2/6	1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112168 AN: 151916 Hom.: 41638 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.892

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.717 AC: 180072 AN: 251044 Hom.: 65321 AF XY: 0.714 AC XY: 96919 AN XY: 135670

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.882

Gnomad EAS exome AF: 0.589

Gnomad SAS exome AF: 0.641

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.742

GnomAD4 exome AF: 0.727 AC: 1061572 AN: 1459742 Hom.: 388127 Cov.: 35 AF XY: 0.725 AC XY: 526885 AN XY: 726326

Gnomad4 AFR exome AF: 0.773

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.882

Gnomad4 EAS exome AF: 0.574

Gnomad4 SAS exome AF: 0.644

Gnomad4 FIN exome AF: 0.693

Gnomad4 NFE exome AF: 0.735

Gnomad4 OTH exome AF: 0.739

GnomAD4 genome AF: 0.738 AC: 112245 AN: 152034 Hom.: 41663 Cov.: 32 AF XY: 0.733 AC XY: 54492 AN XY: 74292

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.749

Gnomad4 ASJ AF: 0.892

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.643

Gnomad4 FIN AF: 0.694

Gnomad4 NFE AF: 0.731

Gnomad4 OTH AF: 0.770

Alfa AF: 0.740 Hom.: 105861

Bravo AF: 0.746

TwinsUK AF: 0.736 AC: 2728

ALSPAC AF: 0.732 AC: 2823

ESP6500AA AF: 0.765 AC: 3369

ESP6500EA AF: 0.748 AC: 6434

ExAC AF: 0.715 AC: 86816

Asia WGS AF: 0.605 AC: 2108 AN: 3478

EpiCase AF: 0.750

EpiControl AF: 0.755

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.5
DANN	Benign	0.61
DEOGEN2	Benign	0.39	T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.22	T;T;T
MetaRNN	Benign	0.0000047	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Benign	0.19
Sift	Benign	0.82	T;T;T
Sift4G	Benign	0.98	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.046
MPC		0.044
ClinPred		0.011	T
GERP RS		-0.33
Varity_R		0.15
gMVP		0.39

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: rs2274911; hg19: chr6-117130704; COSMIC: COSV59952210;