rs9474143

chr6-52082439-G-Achr6-52082439-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):c.234C>T(p.Asp78=) 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

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 -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 ClinVar 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/exons	MANE	UniProt
PKHD1	NM_138694.4	c.234C>T	p.Asp78=	synonymous_variant	4/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.234C>T	p.Asp78=	synonymous_variant	4/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.234C>T	p.Asp78=	synonymous_variant	4/61	5		A2

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

GnomAD3 exomes AF: 0.283 AC: 71060 AN: 251366 Hom.: 10854 AF XY: 0.287 AC XY: 38920 AN XY: 135846

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 SAS exome AF: 0.364

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

Gnomad4 AFR exome AF: 0.389

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.271

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

Gnomad4 AFR AF: 0.391

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.279

Alfa AF: 0.247 Hom.: 6299

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified Benign:2

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	-	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2019

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

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	-0.86
Cadd	Benign	0.059
Dann	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs9474143; hg19: chr6-51947237; COSMIC: COSV61861118;