rs200509641

chr16-2104548-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.8111C>T(p.Ala2704Val) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,589,016 control chromosomes in the GnomAD database, including 10 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2704T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00092 (10 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.06

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=0.008843273).
• BP6: Variant 16-2104548-G-A is Benign according to our data. Variant chr16-2104548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 440103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104548-G-A is described in Lovd as [Likely_benign]. Variant chr16-2104548-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00092 (1324/1439004) while in subpopulation MID AF= 0.0095 (39/4106). AF 95% confidence interval is 0.00714. There are 10 homozygotes in gnomad4_exome. There are 806 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8111C>T	p.Ala2704Val	missense_variant	22/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8111C>T	p.Ala2704Val	missense_variant	22/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000660 AC: 99 AN: 149894 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00318

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000548

Gnomad OTH AF: 0.000969

GnomAD3 exomes AF: 0.00142 AC: 223 AN: 156602 Hom.: 0 AF XY: 0.00177 AC XY: 150 AN XY: 84578

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.000274

Gnomad ASJ exome AF: 0.000355

Gnomad EAS exome AF: 0.000324

Gnomad SAS exome AF: 0.00531

Gnomad FIN exome AF: 0.000809

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.000920 AC: 1324 AN: 1439004 Hom.: 10 Cov.: 30 AF XY: 0.00113 AC XY: 806 AN XY: 714798

Gnomad4 AFR exome AF: 0.000423

Gnomad4 AMR exome AF: 0.000442

Gnomad4 ASJ exome AF: 0.000233

Gnomad4 EAS exome AF: 0.000408

Gnomad4 SAS exome AF: 0.00538

Gnomad4 FIN exome AF: 0.00166

Gnomad4 NFE exome AF: 0.000546

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.000660 AC: 99 AN: 150012 Hom.: 0 Cov.: 20 AF XY: 0.000710 AC XY: 52 AN XY: 73196

Gnomad4 AFR AF: 0.000346

Gnomad4 AMR AF: 0.000529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.00319

Gnomad4 FIN AF: 0.00171

Gnomad4 NFE AF: 0.000548

Gnomad4 OTH AF: 0.000959

Alfa AF: 0.000849 Hom.: 0

Bravo AF: 0.000635

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000895 AC: 99

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PKD1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 08, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 02, 2016

- -

Polycystic kidney disease, adult type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 02, 2021

- -

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.Ala2704Val variant was identified in 1 of 74 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011). The variant was also identified in dbSNP (ID: rs200509641), LOVD 3.0 (2X), and the ADPKD Mutation Database (likely neutral). The variant was not identified in ClinVar, COGR, or PKD1-LOVD databases. The variant was identified in control databases in 239 of 180276 chromosomes at a frequency of 0.001 in the following populations: South Asian in 125 of 23404 chromosomes (freq. 0.005), European in 70 of 73288 chromosomes (freq. 0.001), Finnish in 19 of 15662 chromosomes (freq. 0.001), Other in 8 of 4820 chromosomes (freq. 0.002), Latino in 7 of 25668 chromosomes (freq. 0.0003), East Asian in 4 of 13122 chromosomes (freq.0.0003), African in 3 of 15856 chromosomes (freq. 0.0002), Ashkenazi Jewish in 3 of 8466 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. This variant was also identified in one individual from our laboratory with a co-occurring pathogenic variant in PKD2 (c.1704dupT, p.Val569CysfsX4), increasing the likelihood this variant does not have clinical significance. The p.Ala2704 residue is not conserved in mammals and four out of five 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 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Benign	0.081	T;T
Sift4G	Benign	0.088	T;T
Polyphen		0.60	P;P
Vest4		0.056
MVP		0.49
ClinPred		0.020	T
GERP RS		-0.39
Varity_R		0.027
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200509641; hg19: chr16-2154549; COSMIC: COSV51913852; COSMIC: COSV51913852;