6-52024890-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_138694.4(PKHD1):​c.4920A>G​(p.Val1640Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,222 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1640V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0052 ( 30 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.44
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 Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 6-52024890-T-C is Benign according to our data. Variant chr6-52024890-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 196805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52024890-T-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-1.44 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKHD1NM_138694.4 linkc.4920A>G p.Val1640Val synonymous_variant Exon 32 of 67 ENST00000371117.8 NP_619639.3 P08F94-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKHD1ENST00000371117.8 linkc.4920A>G p.Val1640Val synonymous_variant Exon 32 of 67 1 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkc.4920A>G p.Val1640Val synonymous_variant Exon 32 of 61 5 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.00283
AC:
431
AN:
152224
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000940
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00531
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00226
AC:
569
AN:
251352
Hom.:
0
AF XY:
0.00219
AC XY:
297
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.000800
Gnomad AMR exome
AF:
0.00136
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.00422
Gnomad OTH exome
AF:
0.00261
GnomAD4 exome
AF:
0.00523
AC:
7639
AN:
1461880
Hom.:
30
Cov.:
34
AF XY:
0.00511
AC XY:
3715
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000597
Gnomad4 AMR exome
AF:
0.00159
Gnomad4 ASJ exome
AF:
0.000268
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.00647
Gnomad4 OTH exome
AF:
0.00546
GnomAD4 genome
AF:
0.00283
AC:
431
AN:
152342
Hom.:
1
Cov.:
32
AF XY:
0.00248
AC XY:
185
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.000938
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00531
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00353
Hom.:
0
Bravo
AF:
0.00288
EpiCase
AF:
0.00496
EpiControl
AF:
0.00326

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:6
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PKHD1: BP4, BP7, BS2 -

Nov 09, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12846734) -

not specified Benign:3
Nov 02, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 06, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:3
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

May 11, 2017
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PKHD1 p.Val1640= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs142465959) as “NA” and ClinVar (benign by Invitae and likely benign by Emory Genetics and Prevention Genetics). The RWTH AAachen University ARPKD database identified a different nucleotide change at the same position, c.4920A>C with the same protein consequence p.Val1640= as a polymorphism. The variant was identified in control databases in 619 of 277084 chromosomes at a frequency of 0.002234, seen in the following populations: European (Non-Finnish) in 521 of 126590 chromosomes (freq. 0.004116), Other in 13 of 6464 chromosomes (freq. 0.002011), Latino in 51 of 34416 chromosomes (freq. 0.001482), African in 21 of 24028 chromosomes (freq. 0.000874), Ashkenazi Jewish in 2 of 10142 chromosomes (freq. 0.0001972), South Asian in 6 of 30782 chromosomes (freq. 0.0001949), and European (Finnish) in 5 of 25792 chromosomes (freq. 0.0001939), but was not seen in the East Asian population, increasing the likelihood this could be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val1640= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.94
DANN
Benign
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs142465959; hg19: chr6-51889688; COSMIC: COSV100583343; API