rs1266923

Positions:

• chr6-51959882-G-A
• chr6-51959882-G-C

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.5896C>T​(p.Leu1966=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0171 in 1,612,946 control chromosomes in the GnomAD database, including 1,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (435 hom., cov: 32)
  • Exomes 𝑓: 0.014 (765 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.81

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=-0.56).
• BP6: Variant 6-51959882-G-A is Benign according to our data. Variant chr6-51959882-G-A is described in ClinVar as [Benign]. Clinvar id is 96414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51959882-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5896C>T	p.Leu1966=	synonymous_variant	36/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5896C>T	p.Leu1966=	synonymous_variant	36/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.5896C>T	p.Leu1966=	synonymous_variant	36/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7585 AN: 151988 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0367

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.0454

GnomAD3 exomes AF: 0.0320 AC: 8041 AN: 251106 Hom.: 362 AF XY: 0.0301 AC XY: 4083 AN XY: 135708

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.0346

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0137 AC: 19941 AN: 1460840 Hom.: 765 Cov.: 31 AF XY: 0.0140 AC XY: 10186 AN XY: 726766

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0980

Gnomad4 SAS exome AF: 0.0343

Gnomad4 FIN exome AF: 0.0569

Gnomad4 NFE exome AF: 0.00253

Gnomad4 OTH exome AF: 0.0243

GnomAD4 genome AF: 0.0501 AC: 7618 AN: 152106 Hom.: 435 Cov.: 32 AF XY: 0.0526 AC XY: 3910 AN XY: 74366

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.0657

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0138 Hom.: 98

Bravo AF: 0.0504

Asia WGS AF: 0.0780 AC: 272 AN: 3478

EpiCase AF: 0.00546

EpiControl AF: 0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 12, 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:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	Variant summary: The c.5896C>T variant involves the alteration of a conserved nucleotide resulting in a synonymous change. 4/5 in silico tools via Alamut predict no significant effect on splicing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 3.2%, predominantly observed in the African subpopulation at a frequency of 13.5% including 82 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in PKHD1 (0.71%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. Publications and a clinical lab have classifed the variant as polymorphism/benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Leu1966Leu variant was identified in 2 of 726 proband chromosomes (frequency: 0.003) from individuals or families with ARPKD, and was present in 22 of 920 control chromosomes (frequency: 0.024) from healthy individuals (Bergmann 2005, Furu 2004, Losekoot 2005, Sharp 2005). The variant was also identified in dbSNP (ID: rs1266923) “With benign allele”, in 1000 Genomes Project in 408 of 5006 chromosomes (frequency: 0.0815), in NHLBI GO Exome Sequencing Project in 35 of 8600 (frequency: 0.004) European American and 586 in 4406 (frequency: 0.1285) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 3934 of 121262 chromosomes (frequency: 0.03) from a population (frequency) of African (0.14), East Asian (0.11), Finnish (0.06), South Asian (0.04), Other (0.03), Latino (0.02), and European Non-Finnish (0.006) individuals. Furthermore, the variant is listed in the ClinVar database as benign by Emory Genetics Laboratory, in the GeneInsight COGR database as benign by LMM, and in RWTH Aachen University ARPKD database as a polymorphism. The p.Leu1966Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant is classified as benign. -

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	-0.56
CADD	Benign	2.8
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1266923; hg19: chr6-51824680; COSMIC: COSV61877425;