rs115072237

Variant names:

• chr6-51658941-T-C
• rs115072237
• NM_138694.4:c.11174+11A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-51658941-T-C
• chr6-51658941-T-G

Variant summary

Our verdict is Benign. The variant received -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:10
• Conservation: PhyloP100: -0.255
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124900615 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 96369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.11174+11A>G		intron_variant	Intron 61 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.11174+11A>G		intron_variant	Intron 61 of 66	1	NM_138694.4	ENSP00000360158.3

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

GnomAD2 exomes AF: 0.0130 AC: 3248 AN: 250712 AF XY: 0.0134

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 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

African (AFR) AF: 0.00253 AC: 83 AN: 32850

American (AMR) AF: 0.00845 AC: 377 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 41 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00708 AC: 606 AN: 85538

European-Finnish (FIN) AF: 0.0128 AC: 681 AN: 53330

Middle Eastern (MID) AF: 0.00297 AC: 17 AN: 5716

European-Non Finnish (NFE) AF: 0.0215 AC: 23230 AN: 1081534

Other (OTH) AF: 0.0162 AC: 957 AN: 59196

GnomAD4 genome AF: 0.0130 AC: 1979 AN: 152222 Hom.: 19 Cov.: 32 AF XY: 0.0126 AC XY: 937 AN XY: 74428

African (AFR) AF: 0.00392 AC: 163 AN: 41560

American (AMR) AF: 0.0136 AC: 207 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4832

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0207 AC: 1405 AN: 68000

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 26, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 09, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.81
DANN	Benign	0.78
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115072237; hg19: chr6-51523739;