6-52017532-C-T

Position:

chr6-52017532-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_138694.4(PKHD1):c.5478G>A(p.Ala1826Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,614,030 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.668

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]

PKHD1 links:

PKHD1 (HGNC:):

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 6-52017532-C-T is Benign according to our data. Variant chr6-52017532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289814.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BP7

Synonymous conserved (PhyloP=-0.668 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.5478G>A	p.Ala1826Ala	synonymous_variant	34/67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.5478G>A	p.Ala1826Ala	synonymous_variant	34/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.5478G>A	p.Ala1826Ala	synonymous_variant	34/61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.000946

AC:

144

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000912

AC:

229

AN:

251020

Hom.:

AF XY:

0.000870

AC XY:

118

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00157

AC:

2297

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1091

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000936

Gnomad4 NFE exome

AF:

0.00195

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000945

AC:

144

AN:

152302

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00148

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000922

EpiCase

AF:

0.00109

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not provided

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.3

DANN

Benign

0.46

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over