rs17667728

Variant names:

• chr6-51648089-A-G
• rs17667728
• NM_138694.4:c.11340T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.577

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 -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	c.11340T>C	p.Pro3780Pro	synonymous_variant	Exon 63 of 67	ENST00000371117.8	NP_619639.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0365 AC: 5546 AN: 152144 Hom.: 120 Cov.: 32

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

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.: 27 AF XY: 0.0392 AC XY: 28369 AN XY: 723266

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.: 32 AF XY: 0.0346 AC XY: 2573 AN XY: 74442

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.: 67

Bravo AF: 0.0372

Asia WGS AF: 0.0130 AC: 46 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:5

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Sep 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Pro3780= variant was identified in dbSNP (ID: rs17667728) as “With Benign allele”, 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

Other links and lift over

dbSNP: rs17667728; hg19: chr6-51512887; COSMIC: COSV64390175;