rs752776137

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138694.4(PKHD1):​c.8788C>T​(p.Arg2930Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

4
13
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.47
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKHD1NM_138694.4 linkuse as main transcriptc.8788C>T p.Arg2930Trp missense_variant 56/67 ENST00000371117.8 NP_619639.3 P08F94-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKHD1ENST00000371117.8 linkuse as main transcriptc.8788C>T p.Arg2930Trp missense_variant 56/671 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkuse as main transcriptc.8788C>T p.Arg2930Trp missense_variant 56/615 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251002
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135634
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1461118
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
726912
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 08, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2016- -
PKHD1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 03, 2024The PKHD1 c.8788C>T variant is predicted to result in the amino acid substitution p.Arg2930Trp. This variant has been reported in an autosomal recessive polycystic disease cohort (Sharp et al. 2005. PubMed ID: 15805161), though not enough information was provided to determine pathogenicity. The highest population frequency of this variant is 0.010% in individuals of East Asian ancestry in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.30
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.70
D;D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Pathogenic
2.9
M;M
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.7
D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0070
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.51
MutPred
0.52
Loss of disorder (P = 0.027);Loss of disorder (P = 0.027);
MVP
0.99
MPC
0.38
ClinPred
0.94
D
GERP RS
2.4
Varity_R
0.18
gMVP
0.81

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752776137; hg19: chr6-51619591; API