rs765525

Positions:

• chr6-51748379-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.9237G>A​(p.Ala3079Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,552 control chromosomes in the GnomAD database, including 124,516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9635 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114881 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.61

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-51748379-C-T is Benign according to our data. Variant chr6-51748379-C-T is described in ClinVar as [Benign]. Clinvar id is 96441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51748379-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.9237G>A	p.Ala3079Ala	synonymous_variant	58/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.9237G>A	p.Ala3079Ala	synonymous_variant	58/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.9237G>A	p.Ala3079Ala	synonymous_variant	58/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48581 AN: 151888 Hom.: 9638 Cov.: 32

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.420 AC: 105415 AN: 251078 Hom.: 24870 AF XY: 0.422 AC XY: 57266 AN XY: 135678

Gnomad AFR exome AF: 0.0865

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.711

Gnomad SAS exome AF: 0.492

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.365

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.388 AC: 567344 AN: 1461544 Hom.: 114881 Cov.: 44 AF XY: 0.391 AC XY: 284371 AN XY: 727090

Gnomad4 AFR exome AF: 0.0802

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.494

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.374

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.320 AC: 48573 AN: 152008 Hom.: 9635 Cov.: 32 AF XY: 0.331 AC XY: 24561 AN XY: 74264

Gnomad4 AFR AF: 0.0947

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.504

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.315

Alfa AF: 0.363 Hom.: 26347

Bravo AF: 0.311

Asia WGS AF: 0.475 AC: 1654 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.362

ClinVar

Significance: Benign

Submissions summary: Benign:9

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 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKHD1 p.Ala3079= variant was identified in dbSNP (ID: rs765525) “With Benign allele”, ClinVar (classified benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics, Illumina), Clinvitae (3x), RWTH AAachen University ARPKD database (as a polymorphism) and in control databases in 113331 (26391 homozygous) of 276718 chromosomes at a frequency of 0.4 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2095 (96 homozygous) of 24010 chromosomes (freq: 0.09), Other in 2490 (481 homozygous) of 6458 chromosomes (freq: 0.4), Latino in 19685 (5835 homozygous) of 34372 chromosomes (freq: 0.6), European Non-Finnish in 46358 (8579 homozygous) of 126354 chromosomes (freq: 0.4), Ashkenazi Jewish in 3338 (532 homozygous) of 10138 chromosomes (freq: 0.3), East Asian in 13406 (4748 homozygous) of 18840 chromosomes (freq: 0.7), European Finnish in 10817 (2293 homozygous) of 25772 chromosomes (freq: 0.4), and South Asian in 15142 (3827 homozygous) of 30774 chromosomes (freq: 0.5). The variant was not identified in the GeneInsight-COGR, or LOVD 3.0. The p.Ala3079= 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 addition, 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 meets our laboratory criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -

Autosomal recessive polycystic kidney disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
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. -

Polycystic kidney disease 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.1
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs765525; hg19: chr6-51613177; COSMIC: COSV61878225;