chr6-52082439-G-A

Variant names:

• chr6-52082439-G-A
• rs9474143
• NM_138694.4:c.234C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.234C>T​(p.Asp78Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,612,848 control chromosomes in the GnomAD database, including 56,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7247 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49661 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.45
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-52082439-G-A is Benign according to our data. Variant chr6-52082439-G-A is described in CliVar as Benign. Clinvar id is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52082439-G-A is described in CliVar as Benign. Clinvar id is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52082439-G-A is described in CliVar as Benign. Clinvar id is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52082439-G-A is described in CliVar as Benign. Clinvar id is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.234C>T	p.Asp78Asp	synonymous_variant	Exon 4 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.234C>T	p.Asp78Asp	synonymous_variant	Exon 4 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.234C>T	p.Asp78Asp	synonymous_variant	Exon 4 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45583 AN: 151860 Hom.: 7238 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.283 AC: 71060 AN: 251366 AF XY: 0.287

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.255 AC: 371930 AN: 1460868 Hom.: 49661 Cov.: 35 AF XY: 0.257 AC XY: 186713 AN XY: 726782

African (AFR) AF: 0.389 AC: 13023 AN: 33450

American (AMR) AF: 0.212 AC: 9475 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6670 AN: 26132

East Asian (EAS) AF: 0.434 AC: 17245 AN: 39698

South Asian (SAS) AF: 0.359 AC: 30994 AN: 86230

European-Finnish (FIN) AF: 0.297 AC: 15853 AN: 53414

Middle Eastern (MID) AF: 0.294 AC: 1697 AN: 5768

European-Non Finnish (NFE) AF: 0.235 AC: 260590 AN: 1111074

Other (OTH) AF: 0.271 AC: 16383 AN: 60378

GnomAD4 genome AF: 0.300 AC: 45614 AN: 151980 Hom.: 7247 Cov.: 32 AF XY: 0.305 AC XY: 22686 AN XY: 74294

African (AFR) AF: 0.391 AC: 16205 AN: 41436

American (AMR) AF: 0.242 AC: 3693 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 883 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2273 AN: 5138

South Asian (SAS) AF: 0.377 AC: 1814 AN: 4816

European-Finnish (FIN) AF: 0.323 AC: 3408 AN: 10558

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16449 AN: 67972

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.260 Hom.: 11834

Bravo AF: 0.296

Asia WGS AF: 0.399 AC: 1383 AN: 3478

EpiCase AF: 0.245

EpiControl AF: 0.245

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2016

Eurofins Ntd Llc (ga)

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 c.234C>T, p.Asp78Asp variant was identified in 27.44% of 34517 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided Benign:1

Sep 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21790888, 25153916) -

Polycystic kidney disease 4 Benign:1

Jun 19, 2021

Pars Genome Lab

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	-0.86
CADD	Benign	0.059
DANN	Benign	0.43
PhyloP100		-1.5
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9474143; hg19: chr6-51947237; COSMIC: COSV61861118;