rs140065359

Variant names:

• chr6-51906246-G-A
• rs140065359
• NM_138694.4:c.6777C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-51906246-G-A
• chr6-51906246-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_138694.4(PKHD1):​c.6777C>T​(p.Phe2259Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,611,740 control chromosomes in the GnomAD database, including 37 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 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (31 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.33
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 6-51906246-G-A is Benign according to our data. Variant chr6-51906246-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167484.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.6777C>T	p.Phe2259Phe	synonymous_variant	Exon 41 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.6777C>T	p.Phe2259Phe	synonymous_variant	Exon 41 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.6777C>T	p.Phe2259Phe	synonymous_variant	Exon 41 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152124 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00712

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00503 AC: 1262 AN: 250796 AF XY: 0.00466

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00687

Gnomad OTH exome AF: 0.00655

GnomAD4 exome AF: 0.00490 AC: 7146 AN: 1459498 Hom.: 31 Cov.: 28 AF XY: 0.00488 AC XY: 3547 AN XY: 726244

African (AFR) AF: 0.000479 AC: 16 AN: 33394

American (AMR) AF: 0.00269 AC: 120 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86214

European-Finnish (FIN) AF: 0.0143 AC: 762 AN: 53388

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00531 AC: 5891 AN: 1110104

Other (OTH) AF: 0.00415 AC: 250 AN: 60270

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152242 Hom.: 6 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74430

African (AFR) AF: 0.000577 AC: 24 AN: 41564

American (AMR) AF: 0.00131 AC: 20 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00715 AC: 486 AN: 67998

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00555 Hom.: 4

Bravo AF: 0.00288

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00595

EpiControl AF: 0.00551

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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.

not specified Benign:2

Jan 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 21, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.6777C>T (p.Phe2259Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1516/276908 control chromosomes (12 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.014629 (377/25770). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, by applying ACMG rules (BS1, BS2, BP6, BP7) this variant is classified as benign.

not provided Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BP4, BP7, BS2

Nov 27, 2020

GeneDx

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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Phe2259= variant was identified in at least 1 of 252 proband chromosomes (frequency: 0.004) from individuals or families with ARPKD and was present in 1 of 400 control chromosomes (frequency: 0.0025) from healthy individuals (Bergmann_2005_15698423). The variant was also identified in dbSNP (ID: rs140065359) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics) and Invitae, and uncertain signficance by Illumina), and RWTH AAachen University ARPKD database (as unclassified); and not identified in GeneInsight-COGR and LOVD 3.0. The variant was identified in control databases in 1515 (12 homozygous) of 276508 chromosomes at a frequency of 0.005 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 13 of 24020 chromosomes (freq: 0.0005), Other in 41 (1 homozygous) of 6442 chromosomes (freq: 0.006), Latino in 84 of 34304 chromosomes (freq: 0.002), European Non-Finnish in 958 (8 homozygous) of 126228 chromosomes (freq: 0.008), Ashkenazi Jewish in 40 of 10134 chromosomes (freq: 0.004), European Finnish in 377 (3 homozygous) of 25770 chromosomes (freq: 0.01463), and South Asian in 2 of 30774 chromosomes (freq: 0.00007), and was not observed in the East Asian population. The p.Phe2259= 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. 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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	-0.41
CADD	Benign	5.2
DANN	Benign	0.65
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs140065359; hg19: chr6-51771044;