rs79884128

chr16-2110493-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):c.4674G>A(p.Thr1558=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 1,612,318 control chromosomes in the GnomAD database, including 5,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (411 hom., cov: 34)
  • Exomes 𝑓: 0.077 (4977 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.18

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-2110493-C-T is Benign according to our data. Variant chr16-2110493-C-T is described in ClinVar as [Benign]. Clinvar id is 256969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110493-C-T is described in Lovd as [Benign]. Variant chr16-2110493-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4674G>A	p.Thr1558=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4674G>A	p.Thr1558=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9694 AN: 152194 Hom.: 410 Cov.: 34

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0769 AC: 19137 AN: 248748 Hom.: 874 AF XY: 0.0783 AC XY: 10586 AN XY: 135238

Gnomad AFR exome AF: 0.00968

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0968

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.0737

Gnomad FIN exome AF: 0.0878

Gnomad NFE exome AF: 0.0754

Gnomad OTH exome AF: 0.0725

GnomAD4 exome AF: 0.0775 AC: 113080 AN: 1460006 Hom.: 4977 Cov.: 37 AF XY: 0.0781 AC XY: 56758 AN XY: 726292

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.0960

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.0747

Gnomad4 FIN exome AF: 0.0923

Gnomad4 NFE exome AF: 0.0750

Gnomad4 OTH exome AF: 0.0741

GnomAD4 genome AF: 0.0636 AC: 9686 AN: 152312 Hom.: 411 Cov.: 34 AF XY: 0.0646 AC XY: 4808 AN XY: 74468

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.0705

Gnomad4 FIN AF: 0.0851

Gnomad4 NFE AF: 0.0808

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0713 Hom.: 190

Bravo AF: 0.0588

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0769

EpiControl AF: 0.0736

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 01, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.4674G>A, p.Thr1558Thr variant was identified in7.57% of 9015 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.10
Dann	Benign	0.88
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: rs79884128; hg19: chr16-2160494; COSMIC: COSV51916911; COSMIC: COSV51916911;