chr16-2135583-G-T

Position:

• chr16-2135583-G-T

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.107C>A​(p.Pro36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,068,452 control chromosomes in the GnomAD database, including 292 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 31)
  • Exomes 𝑓: 0.023 (252 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.708

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=0.010966539).
• BP6: Variant 16-2135583-G-T is Benign according to our data. Variant chr16-2135583-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2135583-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2436/147704) while in subpopulation NFE AF= 0.0227 (1505/66194). AF 95% confidence interval is 0.0218. There are 40 homozygotes in gnomad4. There are 1217 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.107C>A	p.Pro36His	missense_variant	1/46	ENST00000262304.9	NP_001009944.3
PKD1	NM_000296.4	c.107C>A	p.Pro36His	missense_variant	1/46		NP_000287.4
PKD1	XM_047434208.1	c.107C>A	p.Pro36His	missense_variant	1/48		XP_047290164.1
PKD1	XM_047434209.1	c.107C>A	p.Pro36His	missense_variant	1/47		XP_047290165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.107C>A	p.Pro36His	missense_variant	1/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.107C>A	p.Pro36His	missense_variant	1/46	1		ENSP00000399501	A2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2436 AN: 147602 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.00481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0113

GnomAD4 exome AF: 0.0228 AC: 20963 AN: 920748 Hom.: 252 Cov.: 28 AF XY: 0.0227 AC XY: 9785 AN XY: 430858

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.00891

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.000188

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0165 AC: 2436 AN: 147704 Hom.: 40 Cov.: 31 AF XY: 0.0169 AC XY: 1217 AN XY: 71970

Gnomad4 AFR AF: 0.00479

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0103

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0112

Alfa AF: 0.00605 Hom.: 1

Bravo AF: 0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	This variant is associated with the following publications: (PMID: 22008521, 18640754) -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 28, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Pro36His variant was identified in 20 of 616 proband chromosomes (frequency: 0.03) from individuals or families with ADPKD (with or without family history), and was not identified in 150 control chromosomes from healthy individuals (Reed 2008, Bataille 2011, Peltola 2005, Rossetti 2012). Reed et al. could not classify the variant however the conservation score associated the variant with some evolutionary variability (Reed 2008). The variant was identified in dbSNP (ID: rs560049593) as “With other allele”, ClinVar (classified benign by ARUP, and likely benign by Prevention Genetics and GeneDx), and ADPKD Mutation Database (classified as likely neutral). The variant was not identified in PKD1-LOVD or LOVD 3.0. The variant was identified in control databases in 398 of 26042 chromosomes (3 homozygous) at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 44 of 8250 chromosomes (freq: 0.005), Other in 18 of 744 chromosomes (freq: 0.02), Latino in 2 of 396 chromosomes (freq: 0.005), European Non-Finnish in 266 of 13680 chromosomes (freq: 0.02), Ashkenazi Jewish in 1 of 224 chromosomes (freq: 0.004), European Finnish in 67 of 1126 chromosomes (freq: 0.06); it was not observed in the East Asian, and South Asian populations. The p.Pro36 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His 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) 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. -

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

- -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

This variant is classified as 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	0.26
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.45	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.083
Sift	Benign	0.13	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.28
MVP		0.41
ClinPred		0.25	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.11
gMVP		0.32

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: rs560049593; hg19: chr16-2185584;