6-52053189-G-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.2027C>G(p.Pro676Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,190 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P676S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (6 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.316

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039005876).
• BP6: Variant 6-52053189-G-C is Benign according to our data. Variant chr6-52053189-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 96383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52053189-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0067 (1021/152334) while in subpopulation AFR AF= 0.0229 (951/41570). AF 95% confidence interval is 0.0217. There are 21 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.2027C>G	p.Pro676Arg	missense_variant	21/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.2027C>G	p.Pro676Arg	missense_variant	21/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.2027C>G	p.Pro676Arg	missense_variant	21/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1016 AN: 152216 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00188 AC: 473 AN: 251158 Hom.: 4 AF XY: 0.00153 AC XY: 207 AN XY: 135726

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000707 AC: 1034 AN: 1461856 Hom.: 6 Cov.: 32 AF XY: 0.000623 AC XY: 453 AN XY: 727224

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00670 AC: 1021 AN: 152334 Hom.: 21 Cov.: 32 AF XY: 0.00687 AC XY: 512 AN XY: 74508

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.00736

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: Variant affects a non-conserved nucleotide a results in a replacement of a medium size and hydrophobic Proline (P) with a large size and basic Arginine (R). in silico tools predict the variant to be normal; however these predictions have yet to be confirmed by functional studies. The variant was observed predominantly in the African subcohorts of the ExAC project at an allele frequency of 2.3% (including 3 homozygotes) which exceeds ~3 times the maximal expected allele frequency of a disease causing PKHD1 allele (0.7%) indicating the variant to be in the neutral spectrum. The variant was reported in two autosomal-recessive polycystic kidney disease patients in compound heterozygosity with a potentially pathogenic PKHD1 variant. Clinical laboratories classify variant as Benign/Likely benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	This variant is associated with the following publications: (PMID: 20981092, 21228398, 15698423, 27884173) -

Polycystic kidney disease 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.78
Dann	Benign	0.38
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.20
Sift	Benign	0.67	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0020	B;B
Vest4		0.70
MVP		0.61
MPC		0.063
ClinPred		0.0015	T
GERP RS		-4.4
Varity_R		0.033
gMVP		0.15

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: rs115045643; hg19: chr6-51917987;