6-52050158-G-A

Variant names:

• chr6-52050158-G-A
• rs9370096
• NM_138694.4:c.2278C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.2278C>T​(p.Arg760Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,613,046 control chromosomes in the GnomAD database, including 203,806 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R760H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.41 (14960 hom., cov: 33)
  • Exomes 𝑓: 0.50 (188846 hom.)
• Consequence: PKHD1 NM_138694.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002700
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.479
• Publications: 42 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 -16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in NM_138694.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52050157-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=7.792624E-6).
• BP6: Variant 6-52050158-G-A is Benign according to our data. Variant chr6-52050158-G-A is described in ClinVar as Benign. ClinVar VariationId is 96386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.2278C>T	p.Arg760Cys	missense_variant, splice_region_variant	Exon 22 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.2278C>T	p.Arg760Cys	missense_variant, splice_region_variant	Exon 22 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.2278C>T	p.Arg760Cys	missense_variant, splice_region_variant	Exon 22 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62609 AN: 152006 Hom.: 14962 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.448

GnomAD2 exomes AF: 0.476 AC: 119448 AN: 250924 AF XY: 0.470

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.497

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.501 AC: 732307 AN: 1460922 Hom.: 188846 Cov.: 46 AF XY: 0.498 AC XY: 361609 AN XY: 726782

African (AFR) AF: 0.146 AC: 4896 AN: 33470

American (AMR) AF: 0.636 AC: 28444 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 13029 AN: 26124

East Asian (EAS) AF: 0.369 AC: 14655 AN: 39672

South Asian (SAS) AF: 0.341 AC: 29426 AN: 86228

European-Finnish (FIN) AF: 0.500 AC: 26690 AN: 53412

Middle Eastern (MID) AF: 0.429 AC: 2436 AN: 5680

European-Non Finnish (NFE) AF: 0.525 AC: 583630 AN: 1111272

Other (OTH) AF: 0.482 AC: 29101 AN: 60352

GnomAD4 genome AF: 0.412 AC: 62609 AN: 152124 Hom.: 14960 Cov.: 33 AF XY: 0.409 AC XY: 30409 AN XY: 74364

African (AFR) AF: 0.159 AC: 6611 AN: 41518

American (AMR) AF: 0.568 AC: 8682 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1746 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1977 AN: 5178

South Asian (SAS) AF: 0.332 AC: 1596 AN: 4812

European-Finnish (FIN) AF: 0.472 AC: 4990 AN: 10572

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35522 AN: 67972

Other (OTH) AF: 0.444 AC: 939 AN: 2114

Alfa AF: 0.468 Hom.: 40432

Bravo AF: 0.410

TwinsUK AF: 0.528 AC: 1959

ALSPAC AF: 0.511 AC: 1970

ESP6500AA AF: 0.151 AC: 667

ESP6500EA AF: 0.510 AC: 4388

ExAC AF: 0.465 AC: 56427

Asia WGS AF: 0.322 AC: 1123 AN: 3478

EpiCase AF: 0.517

EpiControl AF: 0.512

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

The c.2278C>T, p.Arg760Cys variant was identified in 46.52% of 56329 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	0.079
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0000078	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N;N
PhyloP100		-0.48
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.22
Sift	Benign	0.23	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0070	B;B
Vest4		0.037
MPC		0.079
ClinPred		0.0099	T
GERP RS		-6.3
Varity_R		0.078
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.11		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: rs9370096; hg19: chr6-51914956; COSMIC: COSV61863770;