22-46257091-C-T

Position:

• chr22-46257091-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006071.2(PKDREJ):​c.6232G>A​(p.Ala2078Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKDREJ NM_006071.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKDREJ	NM_006071.2	c.6232G>A	p.Ala2078Thr	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.6232G>A	p.Ala2078Thr	missense_variant	1/1	6	NM_006071.2	ENSP00000253255.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.6232G>A (p.A2078T) alteration is located in exon 1 (coding exon 1) of the PKDREJ gene. This alteration results from a G to A substitution at nucleotide position 6232, causing the alanine (A) at amino acid position 2078 to be replaced by a threonine (T). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.35		Gain of phosphorylation at A2078 (P = 0.0668);
MVP		0.71
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.38
gMVP		0.42

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: rs753482284; hg19: chr22-46652988;