6-52024560-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.5236+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,612,358 control chromosomes in the GnomAD database, including 1,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 59 hom., cov: 32)

Exomes 𝑓: 0.030 ( 946 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.160

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 6-52024560-T-C is Benign according to our data. Variant chr6-52024560-T-C is described in ClinVar as [Benign]. Clinvar id is 96405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52024560-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.5236+14A>G		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.5236+14A>G		intron_variant		1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.5236+14A>G		intron_variant		5		A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3225

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00540

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00443

Gnomad SAS

AF:

0.0841

Gnomad FIN

AF:

0.00678

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0290

AC:

7243

AN:

249568

Hom.:

181

AF XY:

0.0323

AC XY:

4375

AN XY:

135330

show subpopulations

Gnomad AFR exome

AF:

0.00415

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0192

Gnomad EAS exome

AF:

0.00474

Gnomad SAS exome

AF:

0.0848

Gnomad FIN exome

AF:

0.00911

Gnomad NFE exome

AF:

0.0311

Gnomad OTH exome

AF:

0.0266

GnomAD4 exome

AF:

0.0304

AC:

44348

AN:

1460068

Hom.:

946

Cov.:

AF XY:

0.0320

AC XY:

23263

AN XY:

726480

show subpopulations

Gnomad4 AFR exome

AF:

0.00433

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0201

Gnomad4 EAS exome

AF:

0.00186

Gnomad4 SAS exome

AF:

0.0845

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.0300

Gnomad4 OTH exome

AF:

0.0266

GnomAD4 genome

AF:

0.0212

AC:

3229

AN:

152290

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1609

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00539

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.00444

Gnomad4 SAS

AF:

0.0846

Gnomad4 FIN

AF:

0.00678

Gnomad4 NFE

AF:

0.0295

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0209

Asia WGS

AF:

0.0380

AC:

135

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Autosomal recessive polycystic kidney disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 c.5236+14A>G variant was identified as a polymorphism both in proband and control chromosomes at a frequency: 0.05 (Bergmann 2005 , Losekoot 2005 , Sharp 2005 ). The variant was also identified in dbSNP (ID: rs12210725) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.0228 (114 of 5000 chromosomes) 1000 Genomes Project; HAPMAP-CEU in 4 of 120 chromosomes (frequency: 0.3333); HAPMAP-HCB in 2 of 90 chromosomes (frequency: 0.02222); NHLBI GO Exome Sequencing Project in 281 of 8600 European American (freq. 0.0327) and 21 of 4406 (freq. 0.004766) African American chromosomes; Exome Aggregation Consortium database (March 14, 2016) in 3671 (93 homozygous) of 117172 chromosomes (freq. 0.03133) in the following populations: South Asian in 1393 of 16478 chromosomes (freq. 0.08454), European (Non-Finnish) in 1975 of 64092 chromosomes (freq. 0.03082), Latino in 136 of 11480 chromosomes (freq. 0.01185), European (Finnish) in 54 of 6600 chromosomes (freq. 0.008182), and African in 45 of 9138 chromosomes (freq. 0.004924), East Asian in 42 of 8498 (freq. 0.004942) and Other populations in 26 of 886 (freq. 0.02935), indicating the variant a benign polymorphism; Clinvitae (benign by EmyClass); the ClinVar (benign by Emory Genetics), GeneInsight COGR (benign by LMM); RWTH AAachen University ARPKD database (polymorphism). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site but predict creation of a new 5' splice site in this region. This information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

- -

Polycystic kidney disease 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

Cadd

Benign

Dann

Benign

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.42

Position offset: 1

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