rs139520275

Positions:

• chr16-2110116-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.5051C>T​(p.Ser1684Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,609,580 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (19 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.08

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009653002).
• BP6: Variant 16-2110116-G-A is Benign according to our data. Variant chr16-2110116-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110116-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0092 (1402/152338) while in subpopulation AFR AF= 0.0312 (1297/41570). AF 95% confidence interval is 0.0298. There are 19 homozygotes in gnomad4. There are 669 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.5051C>T	p.Ser1684Leu	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.5051C>T	p.Ser1684Leu	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00918 AC: 1397 AN: 152220 Hom.: 19 Cov.: 34

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00259 AC: 629 AN: 242742 Hom.: 13 AF XY: 0.00192 AC XY: 255 AN XY: 132648

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000839

GnomAD4 exome AF: 0.00110 AC: 1602 AN: 1457242 Hom.: 33 Cov.: 35 AF XY: 0.000927 AC XY: 672 AN XY: 724844

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.000882

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00236

GnomAD4 genome AF: 0.00920 AC: 1402 AN: 152338 Hom.: 19 Cov.: 34 AF XY: 0.00898 AC XY: 669 AN XY: 74490

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00281 Hom.: 1

Bravo AF: 0.0110

ESP6500AA AF: 0.0311 AC: 135

ESP6500EA AF: 0.000351 AC: 3

ExAC AF: 0.00308 AC: 370

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely 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

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.Ser1684Leu variant was identified in 2 of 534 proband chromosomes (frequency: 0.0037) from individuals or families with (Bataille 2011, Rossetti 2012). The variant was also identified in dbSNP (ID: rs139520275) “with likely benign allele,” ClinVar (as likely benign by Prevention Genetics), and ADPKD Mutation Database (4x as likely neutral, found with a truncating mutation). The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases. The variant was identified in control databases in 901 of 269958 chromosomes at a frequency of 0.003338 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 807 of 23162 chromosomes (freq: 0.035). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Bataille (2011) classify the variant as a polymorphism. The p.Ser1684Leu residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the PKD domain Polycystin cation channel PKD/Chitinase domain functional domains, but this is also uninformative. 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. -

Autosomal dominant polycystic kidney disease Benign:1

Likely 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

Feb 13, 2020

This variant is associated with the following publications: (PMID: 22008521) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.092
Sift	Benign	0.25	T;T
Sift4G	Benign	0.083	T;T
Polyphen		0.011	B;B
Vest4		0.29
MVP		0.62
ClinPred		0.0083	T
GERP RS		2.1
Varity_R		0.057
gMVP		0.43

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: rs139520275; hg19: chr16-2160117;