rs150925674

chr6-51772763-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):c.8581A>G(p.Ser2861Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,595,750 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0032 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (20 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.933

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011273086).
• BP6: Variant 6-51772763-T-C is Benign according to our data. Variant chr6-51772763-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215542.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=1}. Variant chr6-51772763-T-C is described in Lovd as [Likely_benign]. Variant chr6-51772763-T-C is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.8581A>G	p.Ser2861Gly	missense_variant	55/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.8581A>G	p.Ser2861Gly	missense_variant	55/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.8581A>G	p.Ser2861Gly	missense_variant	55/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 151902 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00328 AC: 823 AN: 250704 Hom.: 7 AF XY: 0.00341 AC XY: 462 AN XY: 135498

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00303 AC: 4378 AN: 1443730 Hom.: 20 Cov.: 26 AF XY: 0.00308 AC XY: 2214 AN XY: 719496

Gnomad4 AFR exome AF: 0.000484

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000424

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.00325 AC: 494 AN: 152020 Hom.: 3 Cov.: 31 AF XY: 0.00390 AC XY: 290 AN XY: 74278

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000526

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00245 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.00306

EpiControl AF: 0.00303

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 26695994, 19914852, 12874454, 27225849, 24162162, 23582048, 15805161, 15698423, 14741187, 26385851, 30507656) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PKHD1: BP4 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The PKHD1 c.8581A>G (p.Ser2861Gly) variant involves the alteration of a non-conserved nucleotide and 2/3 in silico tools (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome for this variant. This variant was found in 1011/276778 control chromosomes, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.019838 (509/25658). This frequency is about 3 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. The variant of interest has been reported in multiple affected individuals including individuals that were compound heterozygotes for two pathogenic variants, further supporting the variant of interest being in the benign spectrum. The reports of its occurence in cis with another pathogenic variant in patients with a confirmed second disease causing variation, provides further supporting evidence in favor of its benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as Benign. -

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	14
Dann	Benign	0.81
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N;N
MutationTaster	Benign	0.80	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.3	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.77	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.011	B;B
Vest4		0.76
MVP		0.71
MPC		0.074
ClinPred		0.0046	T
GERP RS		2.1
Varity_R		0.073
gMVP		0.89

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: rs150925674; hg19: chr6-51637561;