rs148496347

chr16-2108502-G-Achr16-2108502-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001009944.3(PKD1):c.6665C>T(p.Ala2222Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,608,720 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2222A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.63

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03919947).
• BP6: Variant 16-2108502-G-A is Benign according to our data. Variant chr16-2108502-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447995.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr16-2108502-G-A is described in Lovd as [Benign]. Variant chr16-2108502-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.6665C>T	p.Ala2222Val	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.6665C>T	p.Ala2222Val	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000659 AC: 157 AN: 238062 Hom.: 0 AF XY: 0.000640 AC XY: 84 AN XY: 131308

Gnomad AFR exome AF: 0.0000699

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.00140 AC: 2042 AN: 1456410 Hom.: 1 Cov.: 34 AF XY: 0.00135 AC XY: 980 AN XY: 724540

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.000751

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74480

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000744

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00165 AC: 14

ExAC AF: 0.000481 AC: 57

EpiCase AF: 0.00142

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2020	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PKD1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.6665C>T (p.A2222V) alteration is located in exon 15 (coding exon 15) of the PKD1 gene. This alteration results from a C to T substitution at nucleotide position 6665, causing the alanine (A) at amino acid position 2222 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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.Ala2222Val variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs148496347) as “NA”, ADPKD Mutation Database (classified as likely neutral), the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008), the NHLBI GO Exome Sequencing Project in 14 of 8480 European American alleles, the Exome Aggregation Consortium database (March 14, 2016) in 49 of 106856 chromosomes (freq. 0.0005) in the following populations: European in 48 of 57726 chromosomes (freq. 0.0008), African in 1 of 7870 chromosomes (freq. 0.0001), but was not seen in Asian, Finish, Latino and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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.Ala2222 residue is conserved across mammals and other organisms, however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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. -

PKD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2019

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	0.098
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.58	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.10
Sift	Benign	0.13	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.30	B;P
Vest4		0.21
MVP		0.81
ClinPred		0.022	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.68

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: rs148496347; hg19: chr16-2158503;