rs62406036

chr6-52056905-A-G

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.1587T>C(p.Asn529=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0681 in 1,612,956 control chromosomes in the GnomAD database, including 4,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (298 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3902 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.02

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=-0.48).
• BP6: Variant 6-52056905-A-G is Benign according to our data. Variant chr6-52056905-A-G is described in ClinVar as [Benign]. Clinvar id is 96378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52056905-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.1587T>C	p.Asn529=	synonymous_variant	17/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.1587T>C	p.Asn529=	synonymous_variant	17/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.1587T>C	p.Asn529=	synonymous_variant	17/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8040 AN: 152054 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0997

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0667

Gnomad OTH AF: 0.0432

GnomAD3 exomes AF: 0.0665 AC: 16707 AN: 251138 Hom.: 669 AF XY: 0.0699 AC XY: 9488 AN XY: 135718

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0980

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0563

GnomAD4 exome AF: 0.0697 AC: 101863 AN: 1460784 Hom.: 3902 Cov.: 31 AF XY: 0.0706 AC XY: 51277 AN XY: 726778

Gnomad4 AFR exome AF: 0.00998

Gnomad4 AMR exome AF: 0.0333

Gnomad4 ASJ exome AF: 0.0499

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.0970

Gnomad4 FIN exome AF: 0.0911

Gnomad4 NFE exome AF: 0.0691

Gnomad4 OTH exome AF: 0.0650

GnomAD4 genome AF: 0.0528 AC: 8039 AN: 152172 Hom.: 298 Cov.: 32 AF XY: 0.0552 AC XY: 4105 AN XY: 74404

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0395

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0997

Gnomad4 NFE AF: 0.0667

Gnomad4 OTH AF: 0.0432

Alfa AF: 0.0603 Hom.: 192

Bravo AF: 0.0459

Asia WGS AF: 0.106 AC: 368 AN: 3474

EpiCase AF: 0.0613

EpiControl AF: 0.0638

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, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2013	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

Thec.1587T>C, p.Asn529Asn variant was identified in 6.79% of 8219 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

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	-0.48
Cadd	Benign	6.2
Dann	Benign	0.87

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: rs62406036; hg19: chr6-51921703; COSMIC: COSV61877195;