rs144634185

chr16-2109485-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):c.5682C>T(p.Ala1894=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,609,434 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (36 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.171

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=-0.53).
• BP6: Variant 16-2109485-G-A is Benign according to our data. Variant chr16-2109485-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109485-G-A is described in Lovd as [Benign]. Variant chr16-2109485-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.171 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00499 (761/152354) while in subpopulation NFE AF= 0.00851 (579/68024). AF 95% confidence interval is 0.00794. There are 4 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 762 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.5682C>T	p.Ala1894=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.5682C>T	p.Ala1894=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 762 AN: 152236 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00443 AC: 1069 AN: 241270 Hom.: 3 AF XY: 0.00451 AC XY: 596 AN XY: 132240

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.00142

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.00719

Gnomad OTH exome AF: 0.00657

GnomAD4 exome AF: 0.00676 AC: 9851 AN: 1457080 Hom.: 36 Cov.: 35 AF XY: 0.00654 AC XY: 4743 AN XY: 724834

Gnomad4 AFR exome AF: 0.000988

Gnomad4 AMR exome AF: 0.00408

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00813

Gnomad4 OTH exome AF: 0.00574

GnomAD4 genome AF: 0.00499 AC: 761 AN: 152354 Hom.: 4 Cov.: 33 AF XY: 0.00479 AC XY: 357 AN XY: 74496

Gnomad4 AFR AF: 0.00163

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00851

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00662 Hom.: 3

Bravo AF: 0.00512

EpiCase AF: 0.00698

EpiControl AF: 0.00803

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PKD1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	This variant is associated with the following publications: (PMID: 22383692, 17574468, 11967008) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 28, 2021	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 20, 2020	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala1894Ala variant was identified in 7 of 714 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Rossetti_2012, Rossetti_2002, Garcia-Gonzalez_2007). The variant was identified in dbSNP (ID: rs144634185) as “With Likely benign allele”, ClinVar (classified benign by ARUP Laboratories and likely benign by Prevention Genetics), ADPKD Mutation Database (classified likely neutral), and in control databases in 1215 of 268382 chromosomes (5 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 36 of 22920 chromosomes (freq: 0.002), Other in 38 of 6304 chromosomes (freq: 0.006), Latino in 144 of 34192 chromosomes (freq: 0.004), European Non-Finnish in 898 (4 homozygous) of 121596 chromosomes (freq: 0.007), Ashkenazi Jewish in 14 of 9944 chromosomes (freq: 0.001), East Asian in 1 of 18624 chromosomes (freq: 0.00005), European Finnish in 39 of 24354 chromosomes (freq: 0.002), and South Asian in 45 (1 homozygous) of 30448 chromosomes (freq: 0.001). The variant was not identified in the COGR, LOVD 3.0, or PKD1-LOVD databases. The p.Ala1894= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.7749delC, p.Leu2584Serfsx36) increasing the likelihood the variant does not have clinical significance. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.7
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs144634185; hg19: chr16-2159486; COSMIC: COSV99239493; COSMIC: COSV99239493;