rs150838488

chr6-51960010-T-Achr6-51960010-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138694.4(PKHD1):c.5768A>T(p.Gln1923Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,366 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1923Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 1.43

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028435498).
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.5768A>T	p.Gln1923Leu	missense_variant	36/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.5768A>T	p.Gln1923Leu	missense_variant	36/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.5768A>T	p.Gln1923Leu	missense_variant	36/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152038 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000722 AC: 181 AN: 250646 Hom.: 0 AF XY: 0.000753 AC XY: 102 AN XY: 135484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00146 AC: 2138 AN: 1461210 Hom.: 4 Cov.: 32 AF XY: 0.00137 AC XY: 996 AN XY: 726912

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152156 Hom.: 6 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74382

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000772 Hom.: 0

Bravo AF: 0.00178

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.00142

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15698423, 26489027, 34426522) -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive polycystic kidney disease Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PKHD1 c.5768A>T (p.Gln1923Leu) variant is a missense variant that has been reported in a compound heterozygous state in one patient with polycystic kidney disease (Bergmann et al. 2005). The p.Gln1923Leu variant was absent from 200 controls but is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Gln1923Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 16, 2022

Variant summary: PKHD1 c.5768A>T (p.Gln1923Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 257770 control chromosomes (gnomAD, publications), predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00072 vs 0.0071), allowing no conclusion about variant significance. c.5768A>T has been reported in the literature in individuals affected with Kidney Disease (Bergmann_2005, Nicolaou_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

PKHD1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The PKHD1 c.5768A>T variant is predicted to result in the amino acid substitution p.Gln1923Leu. This variant was reported, along with a second missense variant in the same gene, in an individual with polycystic kidney disease (Bergmann et al. 2005. PubMed ID: 15698423); however, in another study, this variant was not found to be significantly enriched in an affected patient population (Miko et al. 2021. PubMed ID: 34405919, supplementary data). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	19
Dann	Benign	0.82
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.51
Sift	Benign	1.0	T;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.024	B;B
Vest4		0.59
MVP		0.87
MPC		0.064
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.75

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: rs150838488; hg19: chr6-51824808;