rs1288017883

Positions:

• chr6-52065011-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000371117.8(PKHD1):​c.920T>C​(p.Ile307Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,453,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PKHD1 ENST00000371117.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.12

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain IPT/TIG 3 (size 76) in uniprot entity PKHD1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in ENST00000371117.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 6-52065011-A-G is Pathogenic according to our data. Variant chr6-52065011-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551925.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr6-52065011-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.920T>C	p.Ile307Thr	missense_variant	13/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.920T>C	p.Ile307Thr	missense_variant	13/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.920T>C	p.Ile307Thr	missense_variant	13/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250814 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453866 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723546

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:2 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 307 of the PKHD1 protein (p.Ile307Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15108281, 19914852). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551925). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.93		Gain of disorder (P = 0.0138);Gain of disorder (P = 0.0138);
MVP		0.98
MPC		0.42
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.85

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: rs1288017883; hg19: chr6-51929809;