rs143312683

chr16-2100066-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_001009944.3(PKD1):c.9718G>A(p.Ala3240Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,599,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.487

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 -7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 181) in uniprot entity PKD1_HUMAN there are 61 pathogenic changes around while only 23 benign (73%) in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.020558327).
• BP6: Variant 16-2100066-C-T is Benign according to our data. Variant chr16-2100066-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522080.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}. Variant chr16-2100066-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.9718G>A	p.Ala3240Thr	missense_variant	29/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.9718G>A	p.Ala3240Thr	missense_variant	29/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000403 AC: 91 AN: 225760 Hom.: 0 AF XY: 0.000397 AC XY: 49 AN XY: 123394

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.0000941

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.000389

Gnomad NFE exome AF: 0.000758

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000518 AC: 750 AN: 1447502 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 387 AN XY: 719352

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000118

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.000564

Gnomad4 NFE exome AF: 0.000620

Gnomad4 OTH exome AF: 0.000335

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74504

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000935 AC: 8

ExAC AF: 0.000442 AC: 53

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The c.9718G>A (p.A3240T) alteration is located in exon 29 (coding exon 29) of the PKD1 gene. This alteration results from a G to A substitution at nucleotide position 9718, causing the alanine (A) at amino acid position 3240 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala3240Thr variant was identified in 2 of 572 proband chromosomes (frequency: 0.003) from Czech and American individuals or families with ADPKD (Obeidova 2014, Rossetti 2012). The variant was also identified in dbSNP (ID: rs143312683) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics), and ADPKD Mutation Database (classified as likely neutral). The variant was not identified in the LOVD 3.0 and PKD1-LOVD databases. The variant was identified in control databases in 119 of 252510 chromosomes at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 21586 chromosomes (freq: 0.0001), Latino in 3 of 31912 chromosomes (freq: 0.00009), European Non-Finnish in 101 of 112472 chromosomes (freq: 0.0009), Ashkenazi Jewish in 1 of 9600 chromosomes (freq: 0.0001), European Finnish in 10 of 24550 chromosomes (freq: 0.0004), and South Asian in 1 of 29260 chromosomes (freq: 0.00003), while it was not observed in the Other or 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.Ala3240 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Thr variant impacts the protein; 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, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 30, 2020

- -

PKD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2023

This variant is classified as likely 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	12
Dann	Benign	0.70
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.078
Sift	Benign	0.29	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.58	P;B
Vest4		0.25
MVP		0.62
ClinPred		0.011	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.022
gMVP		0.17

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: rs143312683; hg19: chr16-2150067;