rs1554144276

chr6-51934193-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_138694.4(PKHD1):c.6038T>C(p.Leu2013Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L2013L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96

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 8 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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.6038T>C	p.Leu2013Pro	missense_variant	37/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.6038T>C	p.Leu2013Pro	missense_variant	37/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.6038T>C	p.Leu2013Pro	missense_variant	37/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 01, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PKHD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 2013 of the PKHD1 protein (p.Leu2013Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.86		Gain of disorder (P = 0.0069);Gain of disorder (P = 0.0069);
MVP		1.0
MPC		0.47
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.97

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: rs1554144276; hg19: chr6-51798991;