rs188914598

chr6-52050144-A-C

Variant summary

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

The NM_138694.4(PKHD1):c.2279+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00844 in 1,613,600 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (71 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.852

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 (BayesDel_noAF=-0.85).
• BP6: Variant 6-52050144-A-C is Benign according to our data. Variant chr6-52050144-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.2279+13T>G		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.2279+13T>G		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.2279+13T>G		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 874 AN: 152214 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00575 AC: 1444 AN: 251050 Hom.: 7 AF XY: 0.00576 AC XY: 782 AN XY: 135698

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00912

Gnomad OTH exome AF: 0.00816

GnomAD4 exome AF: 0.00872 AC: 12739 AN: 1461268 Hom.: 71 Cov.: 32 AF XY: 0.00847 AC XY: 6155 AN XY: 726940

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00646

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00817

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152332 Hom.: 3 Cov.: 33 AF XY: 0.00545 AC XY: 406 AN XY: 74494

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00867

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00703 Hom.: 2

Bravo AF: 0.00636

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 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 13, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PKHD1: BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2021	Variant summary: PKHD1 c.2279+13T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0058 in 251050 control chromosomes, predominantly at a frequency of 0.0091 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 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 Non-Finnish European origin. To our knowledge, no occurrence of c.2279+13T>G 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. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.3
Dann	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs188914598; hg19: chr6-51914942;