6-51772738-G-T

Variant names:

• chr6-51772738-G-T
• rs142522748
• NM_138694.4:c.8606C>A

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.8606C>A​(p.Thr2869Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,597,930 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2869T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 31)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.54

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020076126).
• BP6: Variant 6-51772738-G-T is Benign according to our data. Variant chr6-51772738-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 96436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51772738-G-T is described in Lovd as [Likely_pathogenic]. Variant chr6-51772738-G-T is described in Lovd as [Benign]. Variant chr6-51772738-G-T is described in Lovd as [Likely_benign]. Variant chr6-51772738-G-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1548/151964) while in subpopulation NFE AF = 0.0164 (1114/67924). AF 95% confidence interval is 0.0156. There are 11 homozygotes in GnomAd4. There are 704 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8606C>A	p.Thr2869Lys	missense_variant	Exon 55 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8606C>A	p.Thr2869Lys	missense_variant	Exon 55 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8606C>A	p.Thr2869Lys	missense_variant	Exon 55 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1547 AN: 151846 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00849

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00945

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00927 AC: 2325 AN: 250704 AF XY: 0.00908

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0118 AC: 17087 AN: 1445966 Hom.: 152 Cov.: 26 AF XY: 0.0118 AC XY: 8535 AN XY: 720306

Gnomad4 AFR exome AF: 0.00130 AC: 43 AN: 33174

Gnomad4 AMR exome AF: 0.00681 AC: 304 AN: 44614

Gnomad4 ASJ exome AF: 0.0150 AC: 391 AN: 25992

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39536

Gnomad4 SAS exome AF: 0.000791 AC: 68 AN: 85950

Gnomad4 FIN exome AF: 0.00908 AC: 484 AN: 53308

Gnomad4 NFE exome AF: 0.0138 AC: 15115 AN: 1097824

Gnomad4 Remaining exome AF: 0.0109 AC: 654 AN: 59840

GnomAD4 genome AF: 0.0102 AC: 1548 AN: 151964 Hom.: 11 Cov.: 31 AF XY: 0.00948 AC XY: 704 AN XY: 74232

Gnomad4 AFR AF: 0.00260 AC: 0.00260153 AN: 0.00260153

Gnomad4 AMR AF: 0.00855 AC: 0.00854813 AN: 0.00854813

Gnomad4 ASJ AF: 0.0187 AC: 0.0187428 AN: 0.0187428

Gnomad4 EAS AF: 0.000195 AC: 0.000194553 AN: 0.000194553

Gnomad4 SAS AF: 0.00104 AC: 0.00103821 AN: 0.00103821

Gnomad4 FIN AF: 0.00945 AC: 0.00945001 AN: 0.00945001

Gnomad4 NFE AF: 0.0164 AC: 0.0164007 AN: 0.0164007

Gnomad4 OTH AF: 0.0104 AC: 0.0104364 AN: 0.0104364

Alfa AF: 0.0141 Hom.: 54

Bravo AF: 0.00889

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00930 AC: 1129

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.0138

EpiControl AF: 0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:5

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 27, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

not provided Benign:4

Oct 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12874454, 15108277, 15805161, 15698423, 28492530, 12846734, 16133180, 25701400) -

Jan 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.8606C>A affects a conserved nucleotide, resulting in amino acid change from Thr to Lys. 3/4 in-silico tools predict this variant to be damaging, however, these in silico predictions have not been validated by any in vitro/vivo functional studies yet. This variant was found in 1133/121106 control chromosomes at a frequency of 0.0093554, predominantly observed in non-Finnish European subpopulation in ExAC with MAF of 0.01445 (962/66572 chr) with total 14 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0070711), suggesting this variant is a benign polymorphism in non-Finnish Europeans. Two clinical laboratories via ClinVar classified this variant as benign/likely benign. Autosomal Recessive Polycystic Kidney Disease database and multiple literature publications list this variant as polymorphism. Considering all, this variant was classified as Likely Benign until more information becomes available. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BS1, BS2 -

not specified Benign:2

Jul 15, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Thr2869Lys variant was identified in 5 of 122 proband chromosomes (frequency: 0.041) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroli’s disease, and was present in 5 of 420 control chromosomes (frequency: 0.012) from healthy individuals (Rosetti 2003, Furu 2004, Sharp 2005). Kindreds in which the variant was identified also carried multiple other variants, with at least one being pathogenic (Rosetti 2003). The variant was also identified in dbSNP (ID: rs142522748) “With likely benign allele”, Clinvitae database (classifications benign/likely benign), the ClinVar database (classification benign by Emory Genetics Laboratory, and likely benign by Counsyl), RWTH AAachen University ARPKD database (classified as a polymorphism) and PKHD1-LOVD (not classified); in the 1000 Genomes Project in 21 of 5000 chromosomes (frequency: 0.0042), HAPMAP populations EUR in 9 of 1006 chromosomes (frequency: 0.0089) and AMR in 12 of 694 chromosomes (frequency: 0.0173), NHLBI GO Exome Sequencing Project in 115 of 8600 European American alleles (frequency: 0.0134) and in 8 of 4406 African American alleles (frequency: 0.0018), and in the Exome Aggregation Consortium database (March 14, 2016) in 976 of 66572 chromosomes (frequency: 0.0145) from a population of European (Non-Finnish) individuals, and none in the East Asian, Other, African, Latino, South Asian, or European (Finnish) populations. The p.Thr2869 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as likely benign. -

Caroli disease Benign:1

May 05, 2021

Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.98	D;D
Vest4		0.84
MVP		0.99
MPC		0.40
ClinPred		0.035	T
GERP RS		4.9
Varity_R		0.82
gMVP		0.95
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs142522748; hg19: chr6-51637536; COSMIC: COSV61868162;