NM_138694.4:c.3785C>T

Variant names:

• chr6-52026025-G-A
• rs9296669
• NM_138694.4:c.3785C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1262P) has been classified as Uncertain significance.

• 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
• Publications: 44 publications found

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]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 96399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.3785C>T	p.Ala1262Val	missense_variant	Exon 32 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.3785C>T	p.Ala1262Val	missense_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.3785C>T	p.Ala1262Val	missense_variant	Exon 32 of 61	5		ENSP00000341097.4

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

GnomAD2 exomes AF: 0.479 AC: 119919 AN: 250462 AF XY: 0.474

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 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

African (AFR) AF: 0.144 AC: 4816 AN: 33478

American (AMR) AF: 0.631 AC: 28228 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 12634 AN: 26136

East Asian (EAS) AF: 0.327 AC: 12973 AN: 39698

South Asian (SAS) AF: 0.363 AC: 31351 AN: 86258

European-Finnish (FIN) AF: 0.500 AC: 26652 AN: 53330

Middle Eastern (MID) AF: 0.419 AC: 2415 AN: 5766

European-Non Finnish (NFE) AF: 0.533 AC: 592670 AN: 1111878

Other (OTH) AF: 0.482 AC: 29125 AN: 60392

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

African (AFR) AF: 0.158 AC: 6533 AN: 41478

American (AMR) AF: 0.558 AC: 8523 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1686 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1819 AN: 5168

South Asian (SAS) AF: 0.353 AC: 1698 AN: 4816

European-Finnish (FIN) AF: 0.472 AC: 4987 AN: 10558

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35975 AN: 67968

Other (OTH) AF: 0.433 AC: 911 AN: 2106

Alfa AF: 0.485 Hom.: 64593

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jan 18, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:3

Feb 03, 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

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Polycystic kidney disease 4 Benign:2

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.31
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9296669; hg19: chr6-51890823; COSMIC: COSV61882869;