6-52024560-T-C

Position:

• chr6-52024560-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.160

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]

ACMG classification

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	Protein	UniProt
PKHD1	NM_138694.4	c.5236+14A>G		intron_variant		ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5236+14A>G		intron_variant		1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.5236+14A>G		intron_variant		5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3225 AN: 152172 Hom.: 59 Cov.: 32

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

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.: 32 AF XY: 0.0320 AC XY: 23263 AN XY: 726480

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.: 59 Cov.: 32 AF XY: 0.0216 AC XY: 1609 AN XY: 74460

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.: 14

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

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive polycystic kidney disease Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 26, 2017	- -
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. -

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) “With Benign allele”, 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	15
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

Other links and lift over

dbSNP: rs12210725; hg19: chr6-51889358;