rs2435322

chr6-52010452-A-Cchr6-52010452-A-Gchr6-52010452-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):c.5608T>G(p.Leu1870Val) variant causes a missense change. The variant allele was found at a frequency of 0.993 in 1,597,222 control chromosomes in the GnomAD database, including 787,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70599 hom., cov: 30)
  • Exomes 𝑓: 1.0 (717097 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.28

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=5.6595013E-7).
• BP6: Variant 6-52010452-A-C is Benign according to our data. Variant chr6-52010452-A-C is described in ClinVar as [Benign]. Clinvar id is 96410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52010452-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.5608T>G	p.Leu1870Val	missense_variant	35/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.5608T>G	p.Leu1870Val	missense_variant	35/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.5608T>G	p.Leu1870Val	missense_variant	35/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146193 AN: 152086 Hom.: 70555 Cov.: 30

Gnomad AFR AF: 0.865

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.974

GnomAD3 exomes AF: 0.990 AC: 248675 AN: 251296 Hom.: 123198 AF XY: 0.993 AC XY: 134829 AN XY: 135816

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1439260 AN: 1445018 Hom.: 717097 Cov.: 31 AF XY: 0.997 AC XY: 717668 AN XY: 720126

Gnomad4 AFR exome AF: 0.860

Gnomad4 AMR exome AF: 0.993

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.991

GnomAD4 genome AF: 0.961 AC: 146293 AN: 152204 Hom.: 70599 Cov.: 30 AF XY: 0.963 AC XY: 71696 AN XY: 74416

Gnomad4 AFR AF: 0.865

Gnomad4 AMR AF: 0.986

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.974

Alfa AF: 0.991 Hom.: 117391

Bravo AF: 0.955

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.866 AC: 3814

ESP6500EA AF: 0.999 AC: 8592

ExAC AF: 0.987 AC: 119853

Asia WGS AF: 0.993 AC: 3453 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Leu1870Val variant was identified in RWTH AAachen University ARPKD database as a polymorphism, noting the variant is c.5608G>T (current reference base T), p.Val1870Leu (current reference amino acid Leu), and in control databases in 3683 of 277008 chromosomes at a frequency of 0.0133 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3337 of 24020 chromosomes (freq: 0.1389), Other in 38 of 6468 chromosomes (freq: .0059), Latino in 234 of 34402 chromosomes (freq: .0068), European Non-Finnish in 56 of 126528 chromosomes (freq: .0004), Ashkenazi Jewish in 10 of 10148 chromosomes (freq: .001), East Asian in 1 of 18868 chromosomes (freq: 0.0001), and South Asian in 7 of 30782 chromosomes (freq: 0.0002), while not observed in the European Finnish population. The previously recognized PKHD1 p.Leu1870Val variant was identified dbSNP (ID: rs2435322) “With Benign allele”, ClinVar (classified benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics, Illumina), Clinvitae (3x), and was not identified in the literature or LOVD 3.0. The previously recognized p.Leu1870 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of Val impacting the protein; however, this information is not predictive enough to rule out pathogenicity. 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 28509106) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.029
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Benign	0.16
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Benign	5.7e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	1.8	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.037
MPC		0.060
ClinPred		0.010	T
GERP RS		5.6
Varity_R		0.092
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2435322; hg19: chr6-51875250;