rs886042677

Positions:

• chr6-52022809-G-A
• chr6-52022809-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_138694.4(PKHD1):​c.5372C>T​(p.Pro1791Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 1.25

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-52022809-G-A is Pathogenic according to our data. Variant chr6-52022809-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283652.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr6-52022809-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5372C>T	p.Pro1791Leu	missense_variant	33/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5372C>T	p.Pro1791Leu	missense_variant	33/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.5372C>T	p.Pro1791Leu	missense_variant	33/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2023	Reported with a second PKHD1 variant, phase unknown, in a patient with polycystic kidney disease in the published literature (Denamur et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19940839) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -

Autosomal recessive polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Counsyl

May 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.033	D;D
Sift4G	Benign	0.27	T;T
Polyphen		0.96	D;P
Vest4		0.40
MutPred		0.83		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);
MVP		0.99
MPC		0.071
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.83

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: rs886042677; hg19: chr6-51887607;