rs116124750

Variant names:

• chr6-52058606-G-A
• rs116124750
• NM_138694.4:c.1234-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):​c.1234-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,613,502 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (34 hom.)
• Consequence: PKHD1 NM_138694.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009164
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.00700
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-52058606-G-A is Benign according to our data. Variant chr6-52058606-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1766/152258) while in subpopulation AFR AF = 0.0404 (1679/41536). AF 95% confidence interval is 0.0388. There are 32 homozygotes in GnomAd4. There are 823 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1234-5C>T		splice_region_variant, intron_variant	Intron 15 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1234-5C>T		splice_region_variant, intron_variant	Intron 15 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1234-5C>T		splice_region_variant, intron_variant	Intron 15 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1762 AN: 152140 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00308 AC: 767 AN: 249266 AF XY: 0.00226

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00131 AC: 1908 AN: 1461244 Hom.: 34 Cov.: 32 AF XY: 0.00114 AC XY: 826 AN XY: 726958

African (AFR) AF: 0.0418 AC: 1398 AN: 33444

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 173 AN: 1111826

Other (OTH) AF: 0.00325 AC: 196 AN: 60378

GnomAD4 genome AF: 0.0116 AC: 1766 AN: 152258 Hom.: 32 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74474

African (AFR) AF: 0.0404 AC: 1679 AN: 41536

American (AMR) AF: 0.00360 AC: 55 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68014

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00601 Hom.: 9

Bravo AF: 0.0130

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:4

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 22, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15698423, 15805161) -

Apr 26, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant of interest is located at a non-conserved intronic position, not widely known to affect splicing with 3/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 459/120956 (1/263 including 9 homozygotes), predominantly in the African cohort, 410/10276 (1/25 including 8 homozygotes), which exceeds the predicted maximum expected allele frequency for a pathogenic PKHD1 variant of 1/141. Therefore, suggesting that the variant of interest is a common polymorphism found in population(s) of African origin. The variant of interest has been found in affected individuals via publications, although with limited information (ie lack of co-occurrence and co-segregation data) and authors classify the variant as "polymorphism." In addition, a reputable clinical laboratory cites the variant with a "benign" classification. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign until additional information becomes available. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4 Benign:1

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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	-0.80
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		0.0070
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs116124750; hg19: chr6-51923404;