rs13333553

chr16-2103413-A-T

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.8644T>A(p.Trp2882Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,599,366 control chromosomes in the GnomAD database, including 1,050 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (553 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (497 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.124

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=0.0021344721).
• BP6: Variant 16-2103413-A-T is Benign according to our data. Variant chr16-2103413-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 257025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103413-A-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8644T>A	p.Trp2882Arg	missense_variant	23/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8644T>A	p.Trp2882Arg	missense_variant	23/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7130 AN: 152152 Hom.: 553 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0118 AC: 2759 AN: 233310 Hom.: 212 AF XY: 0.00872 AC XY: 1127 AN XY: 129210

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.00896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000394

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00476 AC: 6894 AN: 1447096 Hom.: 497 Cov.: 34 AF XY: 0.00396 AC XY: 2853 AN XY: 720446

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0469 AC: 7139 AN: 152270 Hom.: 553 Cov.: 31 AF XY: 0.0450 AC XY: 3350 AN XY: 74472

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0190 Hom.: 43

Bravo AF: 0.0536

ESP6500AA AF: 0.130 AC: 515

ESP6500EA AF: 0.000770 AC: 6

ExAC AF: 0.0137 AC: 1602

Asia WGS AF: 0.00895 AC: 31 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	This variant is associated with the following publications: (PMID: 17574468, 17582161, 22008521) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 17, 2019

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Trp2882Arg variant is identified in the literature in 3 of 716 proband chromosomes (frequency: 0.004) as a polymorphism from individuals or families with ADPKD, but it was not identified in 442 control chromosomes from healthy individuals (Bataille 2011, Rossetti 2007, Garcia-Gonzalez 2007). In addition the PKD1 p.Glu2966Asp variant was reported as co-occurring with 2 pathogenic PKD1 variants (1470A>G, Y420C and 4262C>T, R1351W) in a proband (Garcia-Gonzalez_2007). The variant was also identified in dbSNP (ID: rs13333553) as “With Benign allele”, Clinvitae (as benign), ClinVar (as benign, by Prevention Genetics), ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 254 of 5008 chromosomes (frequency: 0.050), the NHLBI GO Exome Sequencing Project in 6 of 7794 European American alleles (freq: 0.0007) and in 515 of 3964 African American alleles (freq: 0.13), the genome Aggregation Database (beta, October 19th 2016) in 3124 (239 homozygous) of 236960 chromosomes (freq. 0.013), the Exome Aggregation Consortium database (August 8th 2016) in 1510 (122 homozygous) of 112386 chromosomes (freq. 0.013) in the following populations: African in 1403 of 8206 chromosomes (freq. 0.171), Latino in 80 of 11338 chromosomes (freq. 0.007), other in 5 of 832 chromosomes (freq. 0.006), South Asian in 6 of 16338 chromosomes (freq. 0.0003), and European in 16 of 60860 chromosomes (freq. 0.0002), but was not seen in East Asian and Finnish populations. The variant was identified by our laboratory in 2 individuals with ADPKD, co-occurring with a pathogenic PKD1 variant (c.3489delC, p.Phe1163Leufsx8 and c.2494dupC, p.Arg832ProfsX40), increasing the likelihood that the p.Trp2882Arg variant does not have clinical significance. The p.Trp2882Arg variant was not identified in the PKD1-LOVD, PKD1-LOVD 3.0, COGR and HAPMAP databases. The p.Trp2882 residue is not conserved in mammals and other organisms 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 1 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, this variant meets our laboratory criteria to be classified as 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.1
Dann	Benign	0.46
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.076
Sift	Benign	0.37	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.054	B;B
Vest4		0.10
MutPred		0.46		Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);
ClinPred		0.00031	T
GERP RS		2.6
Varity_R		0.034
gMVP		0.55

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: rs13333553; hg19: chr16-2153414; COSMIC: COSV51920157; COSMIC: COSV51920157;