rs17667728

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_138694.4(PKHD1):c.11340T>C(p.Pro3780Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,604,934 control chromosomes in the GnomAD database, including 1,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 123 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1282 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.577

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 6-51648089-A-G is Benign according to our data. Variant chr6-51648089-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51648089-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.577 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0365 (5552/152262) while in subpopulation AFR AF= 0.0432 (1793/41550). AF 95% confidence interval is 0.0415. There are 123 homozygotes in gnomad4. There are 2573 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 123 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.11340T>C	p.Pro3780Pro	synonymous_variant	Exon 63 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.11340T>C	p.Pro3780Pro	synonymous_variant	Exon 63 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.0365

AC:

5546

AN:

152144

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0432

Gnomad AMI

AF:

0.0681

Gnomad AMR

AF:

0.0238

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0328

AC:

8236

AN:

251050

Hom.:

174

AF XY:

0.0330

AC XY:

4481

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.0437

Gnomad AMR exome

AF:

0.0323

Gnomad ASJ exome

AF:

0.0403

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.0421

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0396

AC:

57460

AN:

1452672

Hom.:

1282

Cov.:

AF XY:

0.0392

AC XY:

28369

AN XY:

723266

show subpopulations

Gnomad4 AFR exome

AF:

0.0401

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0376

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0238

Gnomad4 FIN exome

AF:

0.0167

Gnomad4 NFE exome

AF:

0.0439

Gnomad4 OTH exome

AF:

0.0361

GnomAD4 genome

AF:

0.0365

AC:

5552

AN:

152262

Hom.:

123

Cov.:

AF XY:

0.0346

AC XY:

2573

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0432

Gnomad4 AMR

AF:

0.0240

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0218

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.0426

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0412

Hom.:

Bravo

AF:

0.0372

Asia WGS

AF:

0.0130

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 p.Pro3780= variant was identified in dbSNP (ID: rs17667728) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (as benign by Prevention Genetics and Invitae), Clinvitae (3x as benign), RWTH AAachen University ARPKD database (as a polymorphism). The variant was not identified in the LOVD 3.0 database. The variant was also identified in control databases in 9157 of 276782 chromosomes at a frequency of 0.033084 in the following populations at a frequency greater than 1%: African in 1053 (29 homozygous) of 24034 chromosomes (freq. 0.044), Other in 222 (1 homozygous) of 6454 chromosomes (freq. 0.034), Latino in 1111 (24 homozygous) of 34410 chromosomes (freq. 0.032), European (Non-Finnish) in 5290 (109 homozygous) of 126334 chromosomes (freq. 0.042), Ashkenazi Jewish in 400 (8 homozygous) of 10134 chromosomes (freq. 0.039), European (Finnish) in 361 (5 homozygous) of 25782 chromosomes (freq. 0.014), and South Asian in 713 (20 homozygous) of 30778 chromosomes (freq. 0.023) as well as at frequencies below 1% in East Asian populations in 7 of 18856 chromosomes (freq. 0.0004) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant is widely reported in the literature as a polymorphism, with an allele frequency between 3 and 5% (Bergmann 2004, Bergmann 2005, Furu 2003, Losekoot 2005, Obeidova 2015, Rosetti 2003, Sharp 2005). The p.Pro3780= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.41

DANN

Benign

0.56

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

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