rs113562492

Positions:

• chr6-51775841-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.8521A>G​(p.Met2841Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,582,968 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (22 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.519

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040930808).
• BP6: Variant 6-51775841-T-C is Benign according to our data. Variant chr6-51775841-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188742.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=5}. Variant chr6-51775841-T-C is described in Lovd as [Likely_benign]. Variant chr6-51775841-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00657 (999/152054) while in subpopulation AFR AF= 0.0201 (835/41554). AF 95% confidence interval is 0.019. There are 10 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8521A>G	p.Met2841Val	missense_variant	54/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8521A>G	p.Met2841Val	missense_variant	54/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8521A>G	p.Met2841Val	missense_variant	54/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 993 AN: 151936 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00283 AC: 708 AN: 249804 Hom.: 10 AF XY: 0.00245 AC XY: 331 AN XY: 135060

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00135 AC: 1933 AN: 1430914 Hom.: 22 Cov.: 26 AF XY: 0.00126 AC XY: 898 AN XY: 713738

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000817

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.00657 AC: 999 AN: 152054 Hom.: 10 Cov.: 32 AF XY: 0.00655 AC XY: 487 AN XY: 74330

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.00263

Gnomad4 ASJ AF: 0.0237

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00243 Hom.: 6

Bravo AF: 0.00793

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.00491 AC: 17 AN: 3476

EpiCase AF: 0.000710

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 119/13004=0.91%; Frequency in ESP (AA): 103/4303=2.39% -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2018	Variant summary: PKHD1 c.8521A>G (p.Met2841Val) located in the G8 domain (via InterPro) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 0.0031 in 275668 control chromosomes, predominantly at a frequency of 0.021 within the African subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3-fold 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 African origin. Multiple publications have cited the variant in affected individuals, however, with limited information, i.e. lack of co-occurrence and/or cosegregation data. One publication reports the variant in a compound heterozygote patient, Met2841V/p.Tyr938fs, without providing cosegregation data (Losekoot_2005). Multiple clinical diagnostic laboratories have cited the variant with a classification of "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	PKHD1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2020	This variant is associated with the following publications: (PMID: 22995991, 27884173, 15805161) -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Met2841Val variant was identified in 2 of 228 proband chromosomes (frequency: 0.009) from individuals or unrelated families with ARPKD (Losekoot 2005, Sharp 2005). The variant was also identified in the following databases: dbSNP (ID: rs113562492) as “With other allele”, ClinVar (4x, as benign by EGL Genetics, Invitae and likely benign by Counsyl, and Laboratory for Molecular Medicine), LOVD 3.0 (1x, reported "does not affect function") and RWTH AAachen University ARPKD database (1x). The variant was identified in control databases in 856 of 275468 (12 homozygous) chromosomes at a frequency of 0.003 in the following populations: African in 497 (10 homozygous) of 23972 chromosomes (freq. 0.02), other in 17 of 6418 chromosomes (freq. 0.0026), Latino in 37 of 3490 chromosomes (freq. 0.001), European in 49 of 125822 chromosomes (freq. 0.0004), Ashkenazi Jewish in 254 of 10128 chromosomes (freq. 0.025), South Asian in 2 of 30750 chromosomes (freq. 0.000065), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Met2841Val residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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. The variant is located with the G8 domain functional domain(s) increasing the likelihood that it may have clinical significance. In addition the p.Met2841Val variant was identified in trans with the PKHD1 (c.2812_2813del, p.Tyr938fs) mutation (Losekoot 2005). 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.9
DANN	Benign	0.44
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.23
Sift	Benign	0.085	T;T
Sift4G	Uncertain	0.057	T;T
Polyphen		0.0	B;B
Vest4		0.15
MVP		0.36
MPC		0.063
ClinPred		0.0024	T
GERP RS		-1.1
Varity_R		0.13
gMVP		0.54

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: rs113562492; hg19: chr6-51640639; COSMIC: COSV99049454;