rs770068023

Positions:

• chr6-51753258-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138694.4(PKHD1):​c.8893T>C​(p.Cys2965Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,526 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 6.20

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8893T>C	p.Cys2965Arg	missense_variant	57/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8893T>C	p.Cys2965Arg	missense_variant	57/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8893T>C	p.Cys2965Arg	missense_variant	57/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461526 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2965 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been observed in individuals with PKHD1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 556643). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 16133180, 33532864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2965 of the PKHD1 protein (p.Cys2965Arg). -
Uncertain significance, flagged submission	clinical testing	Counsyl	Feb 13, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.012	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;P
Vest4		0.96
MutPred		0.86		Gain of MoRF binding (P = 0.0034);Gain of MoRF binding (P = 0.0034);
MVP		0.97
MPC		0.49
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.99

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: rs770068023; hg19: chr6-51618056;