rs201349527

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_138694.4(PKHD1):c.1964+17G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,613,548 control chromosomes in the GnomAD database, including 62 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 0.0052 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 60 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.241

Variant links:

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]

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 6-52054021-C-A is Benign according to our data. Variant chr6-52054021-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96382.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=3}. Variant chr6-52054021-C-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 linkuse as main transcript	c.1964+17G>T		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.1964+17G>T		intron_variant		1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.1964+17G>T		intron_variant		5		A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

797

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00884

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00559

AC:

1402

AN:

250830

Hom.:

AF XY:

0.00612

AC XY:

830

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00894

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00725

Gnomad FIN exome

AF:

0.00536

Gnomad NFE exome

AF:

0.00793

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00700

AC:

10224

AN:

1461284

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

5209

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.00831

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00728

Gnomad4 FIN exome

AF:

0.00562

Gnomad4 NFE exome

AF:

0.00772

Gnomad4 OTH exome

AF:

0.00623

GnomAD4 genome

AF:

0.00523

AC:

796

AN:

152264

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

388

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00644

Gnomad4 FIN

AF:

0.00574

Gnomad4 NFE

AF:

0.00884

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00658

Hom.:

Bravo

AF:

0.00412

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2016	Variant summary: The PKHD1 c.1964+17G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on the canonical splice donor site, but 4/5 splice prediction tools predict the gain of cryptic splice donor sites. ESEfinder predicts a gain of a binding motif for splicing enhancer SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 674/121292 control chromosomes (4 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0074681 (497/66550). This frequency is about 1.1 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this intronic variant may be a benign polymorphism found primarily in the non-Finnish Europeans. This variant was reported in at least one ARPKD patient without strong evidence for causality (Obeidova_BMC medical genetics_2015). In addition, one clinical diagnostic laboratory classified this variant as benign, without providing evidence to independently evaluate. Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKHD1: BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 14, 2013

- -

Autosomal recessive polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

PKHD1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Uncertain

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.79

Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over