rs115072237

Positions:

chr6-51658941-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):c.11174+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,580,436 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.018 ( 304 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.255

Variant links:

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 links:

LOC124900615 (HGNC:):

LOC124900615 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 6-51658941-T-C is Benign according to our data. Variant chr6-51658941-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 96369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51658941-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1979/152222) while in subpopulation NFE AF= 0.0207 (1405/68000). AF 95% confidence interval is 0.0198. There are 19 homozygotes in gnomad4. There are 937 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.11174+11A>G		intron_variant		ENST00000371117.8
LOC124900615	XR_926871.3 linkuse as main transcript	n.155+6568T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.11174+11A>G		intron_variant		1	NM_138694.4	P2	P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1979

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0130

AC:

3248

AN:

250712

Hom.:

AF XY:

0.0134

AC XY:

1819

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00738

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0120

GnomAD4 exome

AF:

0.0182

AC:

25992

AN:

1428214

Hom.:

304

Cov.:

AF XY:

0.0180

AC XY:

12797

AN XY:

712738

show subpopulations

Gnomad4 AFR exome

AF:

0.00253

Gnomad4 AMR exome

AF:

0.00845

Gnomad4 ASJ exome

AF:

0.00158

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00708

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0215

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0130

AC:

1979

AN:

152222

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

937

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.0136

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.0207

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive polycystic kidney disease

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2017	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 c.11174+11A>G variant was identified in 4 of 314 proband chromosomes (frequency: 0.01) from Dutch, Czech and European individuals or families with ARPKD and was identified in 5 of 200 chromosomes from healthy individuals (frequency: 0.025) (Obeidova 2015, Losekoot 2005, Bergmann 2005). The variant was also identified in dbSNP (ID: rs115072237) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics) and Prevention Genetics), and RWTH AAachen University ARPKD database (classified as a polymorphism). The variant was also identified in control databases in 3588 of 276422 chromosomes (35 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 89 of 24012 chromosomes (freq: 0.004), Other in 82 (1 homozygous) of 6432 chromosomes (freq: 0.01), Latino in 281 of 34318 chromosomes (freq: 0.008), European Non-Finnish in 2579 (31 homozygous) of 126206 chromosomes (freq: 0.02), Ashkenazi Jewish in 14 of 10138 chromosomes (freq: 0.001), European Finnish in 318 (2 homozygous) of 25726 chromosomes (freq: 0.01), and South Asian in 225 (1 homozygous) of 30778 chromosomes (freq: 0.007). and was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.81

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over