6-52024560-T-C

Variant names:

• chr6-52024560-T-C
• rs12210725
• NM_138694.4:c.5236+14A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 96405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5236+14A>G		intron_variant	Intron 32 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5236+14A>G		intron_variant	Intron 32 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.5236+14A>G		intron_variant	Intron 32 of 60	5		ENSP00000341097.4

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

GnomAD2 exomes AF: 0.0290 AC: 7243 AN: 249568 AF XY: 0.0323

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 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

African (AFR) AF: 0.00433 AC: 145 AN: 33466

American (AMR) AF: 0.0140 AC: 626 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 524 AN: 26130

East Asian (EAS) AF: 0.00186 AC: 74 AN: 39698

South Asian (SAS) AF: 0.0845 AC: 7283 AN: 86202

European-Finnish (FIN) AF: 0.0102 AC: 544 AN: 53164

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5766

European-Non Finnish (NFE) AF: 0.0300 AC: 33359 AN: 1110568

Other (OTH) AF: 0.0266 AC: 1607 AN: 60352

GnomAD4 genome AF: 0.0212 AC: 3229 AN: 152290 Hom.: 59 Cov.: 32 AF XY: 0.0216 AC XY: 1609 AN XY: 74460

African (AFR) AF: 0.00539 AC: 224 AN: 41570

American (AMR) AF: 0.0137 AC: 210 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.0846 AC: 408 AN: 4824

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2005 AN: 68020

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

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

Feb 04, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive polycystic kidney disease Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Polycystic kidney disease 4 Benign:2

Apr 26, 2017

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polycystic kidney disease Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	15
DANN	Benign	0.44
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12210725; hg19: chr6-51889358; COSMIC: COSV107435524;