rs1554229312

Variant names:

• chr6-52084923-C-T
• rs1554229312
• NM_138694.4:c.11G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138694.4(PKHD1):​c.11G>A​(p.Trp4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,094 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PKHD1 NM_138694.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.517
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1139 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-52084923-C-T is Pathogenic according to our data. Variant chr6-52084923-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 557333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.11G>A	p.Trp4*	stop_gained	Exon 2 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.11G>A	p.Trp4*	stop_gained	Exon 2 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.11G>A	p.Trp4*	stop_gained	Exon 2 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454094 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723916

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105012

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 4 Pathogenic:3

Mar 16, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 12, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Pathogenic:1

Mar 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with PKHD1-related disease. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp4*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.20	N
PhyloP100		0.52
Vest4		0.53
GERP RS		4.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554229312; hg19: chr6-51949721;