rs140033417

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):c.7873T>C(p.Leu2625Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,068 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00094 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 47 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0230

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 6-51855931-A-G is Benign according to our data. Variant chr6-51855931-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000939 (143/152332) while in subpopulation SAS AF= 0.0292 (141/4826). AF 95% confidence interval is 0.0253. There are 1 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.7873T>C	p.Leu2625Leu	synonymous_variant	Exon 49 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.7873T>C	p.Leu2625Leu	synonymous_variant	Exon 49 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.7873T>C	p.Leu2625Leu	synonymous_variant	Exon 49 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.000939

AC:

143

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00344

AC:

864

AN:

251392

Hom.:

AF XY:

0.00465

AC XY:

632

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0273

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00164

AC:

2391

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

1701

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0262

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.000939

AC:

143

AN:

152332

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0292

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000147

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Oct 12, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.7873T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.0031 in 277116 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4-folds higher than 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. To our knowledge, no occurrence of c.7873T>C in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Leu2625= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs140033417) as "With Likely benign allele", ClinVar (1x likely benign), and the RWTH AAachen University ARPKD database. The variant was also identified in control databases in 867 of 277116 chromosomes (16 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 24026 chromosomes (freq: 0.00008), Other in 13 of 6464 chromosomes (freq: 0.002), Latino in 2 of 34418 chromosomes (freq: 0.00006), European in 8 of 126612 chromosomes (freq: 0.00006), East Asian in 1 of 18870 chromosomes (freq: 0.00005), and South Asian in 841 of 30782 chromosomes (freq: 0.03). The variant was not observed in the Ashkenazi Jewish or Finnish, populations. The p.Leu2625= 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided

Benign:1

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.52

DANN

Benign

0.45

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