rs117122807

Positions:

• chr6-52054125-T-C

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.1877A>G​(p.Lys626Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,880 control chromosomes in the GnomAD database, including 81 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (75 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.526

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=0.0028981864).
• BP6: Variant 6-52054125-T-C is Benign according to our data. Variant chr6-52054125-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 188736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52054125-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.1877A>G	p.Lys626Arg	missense_variant	20/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.1877A>G	p.Lys626Arg	missense_variant	20/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.1877A>G	p.Lys626Arg	missense_variant	20/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152198 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00284 AC: 713 AN: 251288 Hom.: 15 AF XY: 0.00262 AC XY: 356 AN XY: 135804

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0348

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00178 AC: 2606 AN: 1461564 Hom.: 75 Cov.: 30 AF XY: 0.00177 AC XY: 1289 AN XY: 727098

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0580

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152316 Hom.: 6 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74484

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0374

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00173 Hom.: 9

Bravo AF: 0.00153

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.0170 AC: 59 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Mar 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PKHD1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2020	This variant is associated with the following publications: (PMID: 30566001, 28814334, 28578020, 21790888) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 15, 2015

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Lys626Arg variant was identified in the literature in a case report of a 22 week fetus with findings consistent with ARPKD. Fetal genetic testing was declined, however the father was identified to carry the p.Lys626Arg variant but no additional suspicious variants were identified in the mother or father (Jang 2011). The variant was also identified in dbSNP (ID: rs117122807) “With Benign allele”, ClinVar (classified as benign by Counsyl and Emory Genetics), LOVD 3.0 (unclassified), and the RWTH AAachen University ARPKD database (unclassified) databases, but was not in the Geneinsight-COGR database. The variant was identified in control databases in 734 of 277024 chromosomes (10 homozygous) at a frequency of 0.00265 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Lys626Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.7
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.12
Sift	Benign	0.49	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0010	B;B
Vest4		0.12
MVP		0.71
MPC		0.051
ClinPred		0.0066	T
GERP RS		-0.41
Varity_R		0.037
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs117122807; hg19: chr6-51918923; COSMIC: COSV61886380;