rs886042298

Variant names:

• chr6-52045042-C-G
• NM_138694.4:c.2639G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-52045042-C-G
• chr6-52045042-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_138694.4(PKHD1):​c.2639G>C​(p.Arg880Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,792 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R880C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.68

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 6-52045042-C-G is Pathogenic according to our data. Variant chr6-52045042-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2098389.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.2639G>C	p.Arg880Pro	missense_variant	Exon 25 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.2639G>C	p.Arg880Pro	missense_variant	Exon 25 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.2639G>C	p.Arg880Pro	missense_variant	Exon 25 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726748

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 33940108). 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 arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 880 of the PKHD1 protein (p.Arg880Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.095	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.61
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.51		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.99
MPC		0.45
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-51909840;