rs9474140

chr6-52073444-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):c.527+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,530,006 control chromosomes in the GnomAD database, including 50,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6099 hom., cov: 32)
  • Exomes 𝑓: 0.25 (44860 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.669

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-52073444-A-G is Benign according to our data. Variant chr6-52073444-A-G is described in ClinVar as [Benign]. Clinvar id is 96407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.527+19T>C		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.527+19T>C		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.527+19T>C		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42407 AN: 152034 Hom.: 6092 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.276 AC: 69356 AN: 251244 Hom.: 10291 AF XY: 0.281 AC XY: 38151 AN XY: 135782

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.433

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.249 AC: 342682 AN: 1377854 Hom.: 44860 Cov.: 24 AF XY: 0.252 AC XY: 173732 AN XY: 690668

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.353

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.279 AC: 42426 AN: 152152 Hom.: 6099 Cov.: 32 AF XY: 0.285 AC XY: 21203 AN XY: 74388

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.267

Alfa AF: 0.250 Hom.: 1020

Bravo AF: 0.272

Asia WGS AF: 0.391 AC: 1355 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive polycystic kidney disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 12, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

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	-0.90
Cadd	Benign	1.0
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs9474140; hg19: chr6-51938242; COSMIC: COSV61861111;