6-52024611-G-T

Position:

chr6-52024611-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000371117.8(PKHD1):c.5199C>A(p.Thr1733=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,106 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1733T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 46 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 56 hom. )

Consequence

PKHD1
ENST00000371117.8 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 6-52024611-G-T is Benign according to our data. Variant chr6-52024611-G-T is described in ClinVar as [Benign]. Clinvar id is 241846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52024611-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.11 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.5199C>A	p.Thr1733=	synonymous_variant	32/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.5199C>A	p.Thr1733=	synonymous_variant	32/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.5199C>A	p.Thr1733=	synonymous_variant	32/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2226

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00393

AC:

987

AN:

251182

Hom.:

AF XY:

0.00311

AC XY:

423

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0512

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00164

AC:

2396

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1069

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0542

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.00389

GnomAD4 genome

AF:

0.0147

AC:

2234

AN:

152244

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1042

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0514

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.0170

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 14, 2017	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The c.5199C>A variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 4/5 in silico tools via Alamut predict no significant effect on splicing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.50%, predominantly observed in the African subpopulation at a frequency of 5.2% including 14 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in PKHD1 (0.70%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. One reputable clinical lab has classified the variant as "benign" and multiple publications consider the variant to be a polymorphism. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.011

DANN

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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