rs529066905

chr16-2118216-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001009944.3(PKD1):c.776G>A(p.Cys259Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000261 in 1,533,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.18

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.776G>A	p.Cys259Tyr	missense_variant	5/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.776G>A	p.Cys259Tyr	missense_variant	5/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.776G>A	p.Cys259Tyr	missense_variant	5/46	1		A2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000152 AC: 21 AN: 138576 Hom.: 0 AF XY: 0.000159 AC XY: 12 AN XY: 75438

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.0000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000264 AC: 364 AN: 1381378 Hom.: 0 Cov.: 32 AF XY: 0.000271 AC XY: 185 AN XY: 682724

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.0000837

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000503

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000191

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74392

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.0000618 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17582161, 33502802, Izzi2022[paper], 31738409) -

PKD1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

The PKD1 c.776G>A variant is predicted to result in the amino acid substitution p.Cys259Tyr. This variant was reported in an individual with polycystic kidney disease (Rossetti et al. 2007. PubMed ID: 17582161). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2168217-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Benign	0.93
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.70
MVP		0.75
ClinPred		0.14	T
GERP RS		4.4
Varity_R		0.34
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs529066905; hg19: chr16-2168217;