rs115072237

chr6-51658941-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.255

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]

LOC124900615 (HGNC:):

ACMG classification

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 GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.11174+11A>G		intron_variant		ENST00000371117.8
LOC124900615	XR_926871.3	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	c.11174+11A>G		intron_variant		1	NM_138694.4	P2

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1979 AN: 152104 Hom.: 19 Cov.: 32

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.: 30 AF XY: 0.0134 AC XY: 1819 AN XY: 135556

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.: 27 AF XY: 0.0180 AC XY: 12797 AN XY: 712738

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.: 19 Cov.: 32 AF XY: 0.0126 AC XY: 937 AN XY: 74428

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.: 6

Bravo AF: 0.0121

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Autosomal recessive polycystic kidney disease Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2017	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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) “With Benign allele”, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

- -

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

Other links and lift over

dbSNP: rs115072237; hg19: chr6-51523739; COSMIC: COSV64382658;