rs1210846081

chr6-51959953-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_138694.4(PKHD1):c.5825A>G(p.Asp1942Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000424 in 1,461,330 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). Synonymous variant affecting the same amino acid position (i.e. D1942D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.28

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain G8 1 (size 121) in uniprot entity PKHD1_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.5825A>G	p.Asp1942Gly	missense_variant	36/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.5825A>G	p.Asp1942Gly	missense_variant	36/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.5825A>G	p.Asp1942Gly	missense_variant	36/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461330 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 726984

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease 4 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 16, 2021	- -

Autosomal recessive polycystic kidney disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 08, 2022	For these reasons, this variant has been classified as Pathogenic. 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: 434018). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 12846734, 12874454). 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 aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1942 of the PKHD1 protein (p.Asp1942Gly). -

Polycystic kidney disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Asp1942Gly variant was identified in 3 of 560 proband chromosomes (one homozygous individual) (frequency: 0.013) from unrelated Spanish, American and British individuals or families with ARPKD and was not identified in 620 control chromosomes from healthy individuals (Furu 2004, Sharp 2005, Rosetti 2003, Adeva 2006). Furu et al (2004) identified the mutation in an American caucasian individual in which severe perinatal disease led to neonatal death; with the variant co-occurring with another PKHD1 pathogenic mutation (c.1159_1161delAAT, p.Asn387del). Adeva et al (2006) identified the variant in both of the unrelated parents of an affected child who with neonatal demise. A novel protein domain, G8, was identified, that contains 8 conserved glycine residues in which missense variants (p.Asp1942Gly included) reported to be associated with ARPKD disease are localized in (He 2004). The variant was identified in RWTH AAachen University ARPKD database (classification pathogenic) and PKHD1-LOVD (unclassified); and was not identified in dbSNP, Clinvitae database, the ClinVar database, GeneInsight COGR database, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium database (March 14, 2016). The p.Asp1942 residue is not conserved across mammals, however 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;P
Vest4		0.79
MutPred		0.35		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.97
MPC		0.41
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.74

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: rs1210846081; hg19: chr6-51824751;