rs139752541

Positions:

• chr16-2104622-T-C

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.8037A>G​(p.Val2679=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,575,952 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (20 hom., cov: 20)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.160

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=-0.5).
• BP6: Variant 16-2104622-T-C is Benign according to our data. Variant chr16-2104622-T-C is described in ClinVar as [Benign]. Clinvar id is 440141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104622-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0084 (1236/147126) while in subpopulation AFR AF= 0.0295 (1161/39352). AF 95% confidence interval is 0.0281. There are 20 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8037A>G	p.Val2679=	synonymous_variant	22/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8037A>G	p.Val2679=	synonymous_variant	22/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1232 AN: 147006 Hom.: 19 Cov.: 20

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00359

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.000120

Gnomad OTH AF: 0.00548

GnomAD3 exomes AF: 0.00217 AC: 310 AN: 143122 Hom.: 5 AF XY: 0.00176 AC XY: 137 AN XY: 78012

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000869

Gnomad FIN exome AF: 0.000134

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000702

GnomAD4 exome AF: 0.00102 AC: 1453 AN: 1428826 Hom.: 22 Cov.: 28 AF XY: 0.000868 AC XY: 618 AN XY: 711612

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000711

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00840 AC: 1236 AN: 147126 Hom.: 20 Cov.: 20 AF XY: 0.00835 AC XY: 597 AN XY: 71538

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.00358

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000220

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000120

Gnomad4 OTH AF: 0.00542

Alfa AF: 0.00391 Hom.: 1

Bravo AF: 0.00997

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 02, 2019

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Val2679= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases. The variant was identified in dbSNP (ID: rs139752541) as "With Benign allele ", ClinVar (classified as benign by two clinical laboratories), and in ADPKD Mutation Database (as likely neutral). The variant was identified in control databases in 533 of 166148 chromosomes (10 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 473 of 14834 chromosomes (freq: 0.03), Other in 9 of 4620 chromosomes (freq: 0.0019), Latino in 36 of 25016 chromosomes (freq: 0.0014), European in 12 of 67246 chromosomes (freq: 0.00017), Finnish in 1 of 10730 chromosomes (freq: 0.00009), and South Asian in 2 of 23090 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, and East Asian, populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Val2679= 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2020

- -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2020

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	-0.50
CADD	Benign	7.7
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs139752541; hg19: chr16-2154623;