rs201349527

Variant names:

• chr6-52054021-C-A
• rs201349527
• NM_138694.4:c.1964+17G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-52054021-C-A
• chr6-52054021-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.1964+17G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,613,548 control chromosomes in the GnomAD database, including 62 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 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (60 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.241
• Publications: 2 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 -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-52054021-C-A is Benign according to our data. Variant chr6-52054021-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96382.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00523 (796/152264) while in subpopulation NFE AF = 0.00884 (601/68014). AF 95% confidence interval is 0.00825. There are 2 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1964+17G>T		intron_variant	Intron 20 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1964+17G>T		intron_variant	Intron 20 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1964+17G>T		intron_variant	Intron 20 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 797 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00884

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00559 AC: 1402 AN: 250830 AF XY: 0.00612

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00536

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00700 AC: 10224 AN: 1461284 Hom.: 60 Cov.: 31 AF XY: 0.00717 AC XY: 5209 AN XY: 726974

African (AFR) AF: 0.00105 AC: 35 AN: 33470

American (AMR) AF: 0.00145 AC: 65 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00831 AC: 217 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00728 AC: 628 AN: 86242

European-Finnish (FIN) AF: 0.00562 AC: 300 AN: 53390

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5752

European-Non Finnish (NFE) AF: 0.00772 AC: 8583 AN: 1111558

Other (OTH) AF: 0.00623 AC: 376 AN: 60360

GnomAD4 genome AF: 0.00523 AC: 796 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00521 AC XY: 388 AN XY: 74452

African (AFR) AF: 0.000842 AC: 35 AN: 41544

American (AMR) AF: 0.00183 AC: 28 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00644 AC: 31 AN: 4814

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00884 AC: 601 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00658 Hom.: 1

Bravo AF: 0.00412

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BS2 -

Aug 01, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.1964+17G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on the canonical splice donor site, but 4/5 splice prediction tools predict the gain of cryptic splice donor sites. ESEfinder predicts a gain of a binding motif for splicing enhancer SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 674/121292 control chromosomes (4 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0074681 (497/66550). This frequency is about 1.1 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this intronic variant may be a benign polymorphism found primarily in the non-Finnish Europeans. This variant was reported in at least one ARPKD patient without strong evidence for causality (Obeidova_BMC medical genetics_2015). In addition, one clinical diagnostic laboratory classified this variant as benign, without providing evidence to independently evaluate. Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available. -

not specified Benign:1

Jun 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKHD1-related disorder Benign:1

Aug 30, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Uncertain	24
DANN	Benign	0.50
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201349527; hg19: chr6-51918819;