rs139306706

Positions:

• chr6-51748401-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.9215C>T​(p.Ala3072Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,972 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3072A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.508

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012168914).
• BP6: Variant 6-51748401-G-A is Benign according to our data. Variant chr6-51748401-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96440.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, Uncertain_significance=1}. Variant chr6-51748401-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.9215C>T	p.Ala3072Val	missense_variant	58/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.9215C>T	p.Ala3072Val	missense_variant	58/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.9215C>T	p.Ala3072Val	missense_variant	58/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152122 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00211 AC: 530 AN: 251036 Hom.: 2 AF XY: 0.00248 AC XY: 337 AN XY: 135650

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00859

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000934

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00125 AC: 1820 AN: 1461732 Hom.: 8 Cov.: 34 AF XY: 0.00149 AC XY: 1086 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000761

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00863

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000479

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152240 Hom.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74428

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.000903

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00207 AC: 251

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKHD1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2020	This variant is associated with the following publications: (PMID: 22995991, 15805161) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2021	Variant summary: PKHD1 c.9215C>T (p.Ala3072Val) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of 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 0.0021 in 251036 control chromosomes, predominantly at a frequency of 0.0086 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Although c.9215C>T has been reported in sequencing studies and databases (example, Bergmann_2005), to our knowledge, no occurrence of c.9215C>T in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -

PKHD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2021

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). -

Polycystic kidney disease 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.6
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.27
Sift	Benign	0.048	D;T
Sift4G	Benign	0.069	T;T
Polyphen		0.63	P;B
Vest4		0.086
MVP		0.80
MPC		0.063
ClinPred		0.0099	T
GERP RS		0.28
Varity_R		0.040
gMVP		0.82

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: rs139306706; hg19: chr6-51613199;