rs9296669

chr6-52026025-G-A

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.3785C>T(p.Ala1262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,692 control chromosomes in the GnomAD database, including 208,329 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1262A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (15058 hom., cov: 31)
  • Exomes 𝑓: 0.51 (193271 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.314

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=1.2064343E-5).
• BP6: Variant 6-52026025-G-A is Benign according to our data. Variant chr6-52026025-G-A is described in ClinVar as [Benign]. Clinvar id is 96399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52026025-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.3785C>T	p.Ala1262Val	missense_variant	32/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.3785C>T	p.Ala1262Val	missense_variant	32/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.3785C>T	p.Ala1262Val	missense_variant	32/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62670 AN: 151922 Hom.: 15058 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.479 AC: 119919 AN: 250462 Hom.: 30767 AF XY: 0.474 AC XY: 64241 AN XY: 135514

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.359

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.507

GnomAD4 exome AF: 0.507 AC: 740864 AN: 1461652 Hom.: 193271 Cov.: 58 AF XY: 0.504 AC XY: 366300 AN XY: 727134

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.631

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.327

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.482

GnomAD4 genome AF: 0.412 AC: 62671 AN: 152040 Hom.: 15058 Cov.: 31 AF XY: 0.409 AC XY: 30424 AN XY: 74330

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.529

Gnomad4 OTH AF: 0.433

Alfa AF: 0.500 Hom.: 48529

Bravo AF: 0.409

TwinsUK AF: 0.533 AC: 1976

ALSPAC AF: 0.517 AC: 1993

ESP6500AA AF: 0.150 AC: 660

ESP6500EA AF: 0.517 AC: 4443

ExAC AF: 0.468 AC: 56845

Asia WGS AF: 0.325 AC: 1133 AN: 3478

EpiCase AF: 0.523

EpiControl AF: 0.517

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ala1262Val in exon 32 of PKHD1: This variant is not expected to have clinical significance because it has been identified in 66.59% (7676/11528) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs9296669). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2017	- -

Autosomal recessive polycystic kidney disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

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

-

Thec.3785C>T, p.Ala1262Val variant was identified in 46.98% of 56668 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.098
Dann	Benign	0.90
DEOGEN2	Benign	0.092	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.000012	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.26	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.15
Sift	Benign	0.71	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0	B;B
Vest4		0.022
MPC		0.060
ClinPred		0.0053	T
GERP RS		-1.4
Varity_R		0.020
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9296669; hg19: chr6-51890823; COSMIC: COSV61882869;