rs551353498

chr16-2119356-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.238C>T(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,464,496 control chromosomes in the GnomAD database, including 14 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (14 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040474236).
• BP6: Variant 16-2119356-G-A is Benign according to our data. Variant chr16-2119356-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000528 (693/1312186) while in subpopulation SAS AF= 0.0078 (606/77706). AF 95% confidence interval is 0.00728. There are 14 homozygotes in gnomad4_exome. There are 509 alleles in male gnomad4_exome subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.238C>T	p.Arg80Trp	missense_variant	2/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.238C>T	p.Arg80Trp	missense_variant	2/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.238C>T	p.Arg80Trp	missense_variant	2/46	1		A2
	ENST00000562027.1	n.150G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00158 AC: 216 AN: 136402 Hom.: 7 AF XY: 0.00219 AC XY: 162 AN XY: 74078

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000189

Gnomad SAS exome AF: 0.00934

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000483

GnomAD4 exome AF: 0.000528 AC: 693 AN: 1312186 Hom.: 14 Cov.: 22 AF XY: 0.000781 AC XY: 509 AN XY: 651462

Gnomad4 AFR exome AF: 0.0000995

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.0000404

Gnomad4 EAS exome AF: 0.0000565

Gnomad4 SAS exome AF: 0.00780

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000394

Gnomad4 OTH exome AF: 0.000651

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74470

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00271 AC: 93

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	See Variant Classification Assertion Criteria. -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Arg80Trp variant was not identified in the literature nor was it identified in the ClinVar, COGR, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs551353498), ADPKD Mutation Database (classified indeterminate), and in control databases in 227 of 162048 chromosomes (7 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 4576 chromosomes (freq: 0.0002), Latino in 1 of 24584 chromosomes (freq: 0.00004), European Non-Finnish in 3 of 66780 chromosomes (freq: 0.00005), East Asian in 2 of 11550 chromosomes (freq: 0.0002), and South Asian in 220 (7 homozygous) of 22550 chromosomes (freq: 0.01), it was not observed in the African, Ashkenazi Jewish and European Finnish 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 variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.1391delT, p.Leu464GlnfsX94), increasing the likelihood that the p.Arg80Trp variant does not have clinical significance. The p.Arg80 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 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	0.087
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.010
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.90	P;D
Vest4		0.19
MutPred		0.51		Gain of catalytic residue at L78 (P = 0.0698);Gain of catalytic residue at L78 (P = 0.0698);
MVP		0.64
ClinPred		0.060	T
GERP RS		3.2
Varity_R		0.088
gMVP		0.46

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: rs551353498; hg19: chr16-2169357; COSMIC: COSV51909791; COSMIC: COSV51909791;