rs17752991

Positions:

• chr6-51748124-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138694.4(PKHD1):​c.9492C>T​(p.Ser3164Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,613,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (4 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.39

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]

PKHD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-51748124-G-A is Benign according to our data. Variant chr6-51748124-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51748124-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00108 (165/152262) while in subpopulation EAS AF= 0.0201 (104/5180). AF 95% confidence interval is 0.017. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.9492C>T	p.Ser3164Ser	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.9492C>T	p.Ser3164Ser	synonymous_variant	58/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.9492C>T	p.Ser3164Ser	synonymous_variant	58/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00182 AC: 457 AN: 250854 Hom.: 2 AF XY: 0.00173 AC XY: 234 AN XY: 135528

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.0185

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000972

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000904 AC: 1321 AN: 1461568 Hom.: 4 Cov.: 33 AF XY: 0.000871 AC XY: 633 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000455 Hom.: 0

Bravo AF: 0.00154

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:4

Likely benign, criteria provided, single submitter	literature only	Counsyl	Aug 14, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2019	Variant summary: PKHD1 c.9492C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0018 in 282262 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.018 in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with a frequency of 0.0256 (including 2 homozygotes) that is approximately 3.6-fold higher than the estimated maximal expected allele frequency for a pathogenic PKHD1 variant, further supporting that the variant is a benign polymorphism found primarily in populations of East Asian origin (HGVD). c.9492C>T has also been reported in the literature in healthy control individuals (e.g. Furu 2003, Bergmann 2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.10
DANN	Benign	0.18

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: rs17752991; hg19: chr6-51612922;