rs150597050

Positions:

• chr6-52050268-C-A
• chr6-52050268-C-G
• chr6-52050268-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.2168G>T​(p.Arg723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,614,006 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R723C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (15 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.782

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_138694.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52050269-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195701.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Likely_pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009211212).
• BP6: Variant 6-52050268-C-A is Benign according to our data. Variant chr6-52050268-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 498428.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr6-52050268-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.2168G>T	p.Arg723Leu	missense_variant	22/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.2168G>T	p.Arg723Leu	missense_variant	22/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.2168G>T	p.Arg723Leu	missense_variant	22/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00153 AC: 383 AN: 250710 Hom.: 4 AF XY: 0.00206 AC XY: 279 AN XY: 135598

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000901 AC: 1317 AN: 1461734 Hom.: 15 Cov.: 34 AF XY: 0.00123 AC XY: 891 AN XY: 727196

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00954

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74438

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00173 AC: 210

EpiCase AF: 0.000981

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 17, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2022	Variant summary: PKHD1 c.2168G>T (p.Arg723Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250710 control chromosomes (gnomAD), predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0071), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2168G>T has been reported in the literature in one heterozygous individual affected with Polycystic Kidney Disease, however this individual also carried a different pathogenic variant in the PKD1 gene (c.6040C>T, p.Gln2014Ter) that was determined to be the cause of the patient's phenotype (Eisenberger_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, one as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PKHD1: BP4, BS1, BS2 -

Polycystic kidney disease 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.15	T;T
Sift4G	Benign	0.098	T;T
Polyphen		0.17	B;B
Vest4		0.39
MVP		0.94
MPC		0.21
ClinPred		0.042	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs150597050; hg19: chr6-51915066;