rs9370096

chr6-52050158-G-Achr6-52050158-G-T

Variant summary

Our verdict is Benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). 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

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 -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 2 benign, 6 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 [Likely_pathogenic]. Clinvar id 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 id is 96386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52050158-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PKHD1	NM_138694.4	c.2278C>T	p.Arg760Cys	missense_variant, splice_region_variant	22/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.2278C>T	p.Arg760Cys	missense_variant, splice_region_variant	22/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.2278C>T	p.Arg760Cys	missense_variant, splice_region_variant	22/61	5		A2

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

GnomAD3 exomes AF: 0.476 AC: 119448 AN: 250924 Hom.: 30543 AF XY: 0.470 AC XY: 63730 AN XY: 135628

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 SAS exome AF: 0.337

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

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.636

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.369

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.525

Gnomad4 OTH exome AF: 0.482

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

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.444

Alfa AF: 0.486 Hom.: 30815

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

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	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not specified Benign:2

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

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 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
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
MutationTaster	Benign	0.0071	P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs9370096; hg19: chr6-51914956; COSMIC: COSV61863770;