16-2097499-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):c.10225G>C(p.Val3409Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,601,874 control chromosomes in the GnomAD database, including 807 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (424 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (383 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.115

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=0.0040228367).
• BP6: Variant 16-2097499-C-G is Benign according to our data. Variant chr16-2097499-C-G is described in ClinVar as [Benign]. Clinvar id is 256886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2097499-C-G is described in Lovd as [Benign]. Variant chr16-2097499-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.10225G>C	p.Val3409Leu	missense_variant	33/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.10225G>C	p.Val3409Leu	missense_variant	33/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.10222G>C	p.Val3408Leu	missense_variant	33/46	1		A2
PKD1	ENST00000487932.5	c.*1418G>C		3_prime_UTR_variant, NMD_transcript_variant	20/30	5

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5995 AN: 152214 Hom.: 425 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0107 AC: 2549 AN: 237256 Hom.: 150 AF XY: 0.00763 AC XY: 997 AN XY: 130584

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00837

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.0000696

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00424 AC: 6139 AN: 1449542 Hom.: 383 Cov.: 33 AF XY: 0.00358 AC XY: 2586 AN XY: 721690

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.00931

Gnomad4 ASJ exome AF: 0.000881

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000465

Gnomad4 NFE exome AF: 0.000322

Gnomad4 OTH exome AF: 0.00961

GnomAD4 genome AF: 0.0395 AC: 6015 AN: 152332 Hom.: 424 Cov.: 33 AF XY: 0.0377 AC XY: 2808 AN XY: 74484

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0160 Hom.: 25

Bravo AF: 0.0452

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.124 AC: 543

ESP6500EA AF: 0.000704 AC: 6

ExAC AF: 0.0124 AC: 1494

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000771

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	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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 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.Val3409Leu variant was identified in 7 of 698 proband chromosomes (frequency: 0.010) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012). The variant was identified in dbSNP (ID: rs61747420) as “NA”, ADPKD Mutation Database (classification likely neutral), but was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 257 of 5010 chromosomes (frequency: 0.05), HAPMAP-AFR in 246 of 1322 chromosomes (frequency: 0.1861) and HAPMAP-AMR in 11 of 694 chromosomes (frequency: 0.0159), NHLBI GO Exome Sequencing Project in 6 of 8521 European American alleles (frequency: 0.0007) and in 543 of 4370 African American alleles (frequency: 0.1242), and in the Exome Aggregation Consortium database (March 14, 2016) in 1418 of 112354 chromosomes (freq. 0.013) in the following populations: African in 1301 (84 homozygous) of 8808 chromosomes (freq. 0.15), Latino in 79 of 11296 chromosomes (freq. 0.007), other in 5 of 818 chromosomes (freq. 0.006), European (Non-Finish) in 32 of 60912 chromosomes (freq. 0.0005), and South Asian in 1 of 16374 chromosomes (freq. .00006), but was not seen in East Asian and Finish populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Val3409 residue is 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 5 bases from the 3’ splice site and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the abolishment of the consensus splice site. However, this information is not predictive enough to assume pathogenicity. 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	0.13
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.9
Dann	Benign	0.81
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.043
Sift	Benign	0.31	T;T
Sift4G	Uncertain	0.049	D;D
Polyphen		0.021	B;B
Vest4		0.17
MutPred		0.36		Loss of sheet (P = 0.0357);.;
ClinPred		0.0024	T
GERP RS		2.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.031
gMVP		0.15

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: rs61747420; hg19: chr16-2147500;