rs140065359

chr6-51906246-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_138694.4(PKHD1):c.6777C>T(p.Phe2259=) 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

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 -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 id is 167484.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.6777C>T	p.Phe2259=	synonymous_variant	41/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.6777C>T	p.Phe2259=	synonymous_variant	41/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.6777C>T	p.Phe2259=	synonymous_variant	41/61	5		A2

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

GnomAD3 exomes AF: 0.00503 AC: 1262 AN: 250796 Hom.: 7 AF XY: 0.00466 AC XY: 632 AN XY: 135534

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00415

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

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.00715

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00622 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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Uncertain significance, 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, 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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2017	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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PKHD1: BP4, BP7, BS2 -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs140065359; hg19: chr6-51771044;