rs144557371

chr16-2104639-G-Achr16-2104639-G-C

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.8020C>T(p.Pro2674Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,514,628 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 19)
  • Exomes 𝑓: 0.014 (160 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.911

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=0.0047415793).
• BP6: Variant 16-2104639-G-A is Benign according to our data. Variant chr16-2104639-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104639-G-A is described in Lovd as [Benign]. Variant chr16-2104639-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1574/144690) while in subpopulation NFE AF= 0.0161 (1066/66028). AF 95% confidence interval is 0.0153. There are 16 homozygotes in gnomad4. There are 736 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1573 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8020C>T	p.Pro2674Ser	missense_variant	22/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8020C>T	p.Pro2674Ser	missense_variant	22/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1573 AN: 144572 Hom.: 16 Cov.: 19

Gnomad AFR AF: 0.00209

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.00560

Gnomad ASJ AF: 0.00560

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000682

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00507

GnomAD3 exomes AF: 0.00937 AC: 1214 AN: 129502 Hom.: 7 AF XY: 0.00910 AC XY: 639 AN XY: 70208

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00783

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000962

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0136 AC: 18586 AN: 1369938 Hom.: 160 Cov.: 23 AF XY: 0.0134 AC XY: 9156 AN XY: 684118

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00609

Gnomad4 ASJ exome AF: 0.00733

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000994

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0109 AC: 1574 AN: 144690 Hom.: 16 Cov.: 19 AF XY: 0.0105 AC XY: 736 AN XY: 70198

Gnomad4 AFR AF: 0.00208

Gnomad4 AMR AF: 0.00559

Gnomad4 ASJ AF: 0.00560

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000682

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.00501

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00849

ESP6500AA AF: 0.00137 AC: 4

ESP6500EA AF: 0.00786 AC: 49

ExAC AF: 0.00321 AC: 228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2022	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	This variant is associated with the following publications: (PMID: 22008521, 17574468, 11115377, 32457805) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKD1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 01, 2021	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Pro2674Ser variant was identified in 11 of 586 proband chromosomes (frequency: 0.02) from individuals with Autosomal Dominant Polycystic Kidney Disease (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2001). The variant was identified in dbSNP (rs144557371) as “with other allele”, ClinVar (interpreted as likely benign by our laboratory and 1 other submitter; and as benign by ARUP Laboratories), LOVD 3.0 (observed 2x) and ADPKD Mutation Database (observed 1x). The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 1570 of 151,230 chromosomes (10 homozygous) at a frequency of 0.01, 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 26 of 13,758 chromosomes (freq: 0.002), Other in 52 of 4316 chromosomes (freq: 0.01), Latino in 155 of 24,266 chromosomes (freq: 0.006), European in 986 of 60,346 chromosomes (freq: 0.01), Ashkenazi Jewish in 58 of 7264 chromosomes (freq: 0.008), Finnish in 273 of 9002 chromosomes (freq: 0.03), and South Asian in 20 of 20,846 chromosomes (freq: 0.001); it was not observed in the East Asian population. 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.Pro2674 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	9.5
Dann	Benign	0.75
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.050
Sift	Benign	0.59	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0010	B;B
Vest4		0.11
MVP		0.42
ClinPred		0.0013	T
GERP RS		-2.5
Varity_R		0.034
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs144557371; hg19: chr16-2154640; COSMIC: COSV99032386; COSMIC: COSV99032386;