22-46260349-T-G

Variant names:

• chr22-46260349-T-G
• rs7291444
• NM_006071.2:c.2974A>C

Variant summary

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

The NM_006071.2(PKDREJ):​c.2974A>C​(p.Thr992Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,932 control chromosomes in the GnomAD database, including 25,239 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (6327 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18912 hom.)
• Consequence: PKDREJ NM_006071.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63

Genes affected

PKDREJ (HGNC:9015): (polycystin family receptor for egg jelly) This intronless gene encodes a member of the polycystin protein family. The encoded protein contains 11 transmembrane domains, a receptor for egg jelly (REJ) domain, a G-protein-coupled receptor proteolytic site (GPS) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. This protein may play a role in human reproduction. Alternative splice variants have been described but their biological natures have not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0029013E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKDREJ	NM_006071.2	c.2974A>C	p.Thr992Pro	missense_variant	Exon 1 of 1	ENST00000253255.7	NP_006062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKDREJ	ENST00000253255.7	c.2974A>C	p.Thr992Pro	missense_variant	Exon 1 of 1	6	NM_006071.2	ENSP00000253255.5

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35805 AN: 151994 Hom.: 6315 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0764

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.142 AC: 35762 AN: 251480 Hom.: 4054 AF XY: 0.136 AC XY: 18420 AN XY: 135914

Gnomad AFR exome AF: 0.512

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.0900

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.146 AC: 213642 AN: 1461820 Hom.: 18912 Cov.: 35 AF XY: 0.143 AC XY: 104247 AN XY: 727212

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.0942

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0902

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.236 AC: 35845 AN: 152112 Hom.: 6327 Cov.: 32 AF XY: 0.229 AC XY: 17010 AN XY: 74386

Gnomad4 AFR AF: 0.498

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0750

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.192

Alfa AF: 0.145 Hom.: 2669

Bravo AF: 0.265

TwinsUK AF: 0.142 AC: 526

ALSPAC AF: 0.154 AC: 595

ESP6500AA AF: 0.461 AC: 2031

ESP6500EA AF: 0.146 AC: 1254

ExAC AF: 0.150 AC: 18269

EpiCase AF: 0.153

EpiControl AF: 0.151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.32
DANN	Benign	0.76
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.0050
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.044	B
Vest4		0.040
ClinPred		0.0053	T
GERP RS		-1.3
Varity_R		0.33
gMVP		0.68

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: rs7291444; hg19: chr22-46656246; COSMIC: COSV53551879;