rs7291444

Positions:

• chr22-46260349-T-A
• chr22-46260349-T-G

Variant summary

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

The NM_006071.2(PKDREJ):​c.2974A>T​(p.Thr992Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,614,030 control chromosomes in the GnomAD database, including 371 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T992P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (210 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (161 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=0.0016074479).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKDREJ	NM_006071.2	c.2974A>T	p.Thr992Ser	missense_variant	1/1	ENST00000253255.7	NP_006062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKDREJ	ENST00000253255.7	c.2974A>T	p.Thr992Ser	missense_variant	1/1	6	NM_006071.2	ENSP00000253255.5

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4254 AN: 152030 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0168

GnomAD3 exomes AF: 0.00762 AC: 1916 AN: 251480 Hom.: 78 AF XY: 0.00564 AC XY: 767 AN XY: 135914

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000923

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00304 AC: 4451 AN: 1461882 Hom.: 161 Cov.: 35 AF XY: 0.00271 AC XY: 1969 AN XY: 727242

Gnomad4 AFR exome AF: 0.0937

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000421

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.0280 AC: 4267 AN: 152148 Hom.: 210 Cov.: 32 AF XY: 0.0267 AC XY: 1988 AN XY: 74392

Gnomad4 AFR AF: 0.0951

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.000239 Hom.: 2669

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00920 AC: 1117

EpiCase AF: 0.00136

EpiControl AF: 0.00166

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.027
DANN	Benign	0.38
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.016
Sift	Benign	0.94	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.027
MVP		0.19
ClinPred		0.0043	T
GERP RS		-1.3
Varity_R		0.063
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;