rs149781976

chr6-52058493-C-Gchr6-52058493-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138694.4(PKHD1):c.1342G>C(p.Gly448Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,188 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3
• Conservation: PhyloP100: 0.403

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029243797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.1342G>C	p.Gly448Arg	missense_variant	16/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.1342G>C	p.Gly448Arg	missense_variant	16/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.1342G>C	p.Gly448Arg	missense_variant	16/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00159 AC: 399 AN: 251142 Hom.: 0 AF XY: 0.00141 AC XY: 191 AN XY: 135730

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00206 AC: 3011 AN: 1461868 Hom.: 7 Cov.: 32 AF XY: 0.00200 AC XY: 1454 AN XY: 727236

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74478

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00184

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00190 AC: 231

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 31, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 29642553, 25646624, 28492530, 26489027, 15805161, 21228398, 15698423) -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKHD1 p.Gly448Arg variant was identified in 4 of 618 proband chromosomes (frequency: 0.0065) from individuals with polycystic kidney disease (Eisenberger_2015_PMID:25646624; Bergmann_2005_PMID:15698423; Vora_2017_PMID:28518170; Sharp_2005_PMID:15805161). The variant was identified in dbSNP (ID: rs149781976), LOVD 3.0, ClinVar (classified as uncertain significance by EGL genetics, CeGaT Praxis fuer Humangenetik Tuebingen, Fulgent Genetics and Counsyl for autosomal recessive polycystic kidney disease, and as likely benign by Invitae) and the RWTH AAachen University ARPKD database. The variant was identified in control databases in 445 of 282546 chromosomes at a frequency of 0.001575 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 330 of 128880 chromosomes (freq: 0.002561), Other in 14 of 7220 chromosomes (freq: 0.001939), Latino in 54 of 35432 chromosomes (freq: 0.001524), European (Finnish) in 19 of 25122 chromosomes (freq: 0.000756), South Asian in 16 of 30616 chromosomes (freq: 0.000523), African in 11 of 24968 chromosomes (freq: 0.000441) and Ashkenazi Jewish in 1 of 10358 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Gly448 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -

Autosomal recessive polycystic kidney disease Uncertain:4 Benign:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal dominant polycystic liver disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

PKHD1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	0.10
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.75
MVP		0.90
MPC		0.12
ClinPred		0.040	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.61

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: rs149781976; hg19: chr6-51923291;