17-74439981-A-G

Position:

• chr17-74439981-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022036.4(GPRC5C):​c.205A>G​(p.Ile69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,609,990 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (14 hom.)
• Consequence: GPRC5C NM_022036.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.27

Genes affected

GPRC5C (HGNC:13309): (G protein-coupled receptor class C group 5 member C) The protein encoded by this gene is a member of the type 3 G protein-coupled receptor family. Members of this superfamily are characterized by a signature 7-transmembrane domain motif. The specific function of this protein is unknown; however, this protein may mediate the cellular effects of retinoic acid on the G protein signal transduction cascade. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006281525).
• BP6: Variant 17-74439981-A-G is Benign according to our data. Variant chr17-74439981-A-G is described in ClinVar as [Benign]. Clinvar id is 730067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (1140/152212) while in subpopulation AFR AF= 0.026 (1078/41538). AF 95% confidence interval is 0.0247. There are 15 homozygotes in gnomad4. There are 542 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPRC5C	NM_022036.4	c.205A>G	p.Ile69Val	missense_variant	2/4	ENST00000392627.7	NP_071319.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPRC5C	ENST00000392627.7	c.205A>G	p.Ile69Val	missense_variant	2/4	1	NM_022036.4	ENSP00000376403	P4

Frequencies

GnomAD3 genomes AF: 0.00743 AC: 1130 AN: 152094 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00212 AC: 527 AN: 248746 Hom.: 10 AF XY: 0.00162 AC XY: 218 AN XY: 134692

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000721 AC: 1051 AN: 1457778 Hom.: 14 Cov.: 33 AF XY: 0.000615 AC XY: 446 AN XY: 725382

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152212 Hom.: 15 Cov.: 32 AF XY: 0.00728 AC XY: 542 AN XY: 74416

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00165 Hom.: 4

Bravo AF: 0.00866

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.89
Eigen	Benign	-0.071
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T;.;T
MetaRNN	Benign	0.0063	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.62	.;.;.;N
REVEL	Uncertain	0.29
Sift	Benign	0.23	.;.;.;T
Sift4G	Benign	0.41	T;T;D;T
Polyphen		0.50	.;.;.;P
Vest4		0.26, 0.33, 0.25
MVP		0.38
MPC		0.23
ClinPred		0.049	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs80079984; hg19: chr17-72436120;