6-52024890-T-C

Position:

• chr6-52024890-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_138694.4(PKHD1):​c.4920A>G​(p.Val1640=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,222 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1640V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (30 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.44

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-52024890-T-C is Benign according to our data. Variant chr6-52024890-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 196805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52024890-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.4920A>G	p.Val1640=	synonymous_variant	32/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.4920A>G	p.Val1640=	synonymous_variant	32/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.4920A>G	p.Val1640=	synonymous_variant	32/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00226 AC: 569 AN: 251352 Hom.: 0 AF XY: 0.00219 AC XY: 297 AN XY: 135834

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00523 AC: 7639 AN: 1461880 Hom.: 30 Cov.: 34 AF XY: 0.00511 AC XY: 3715 AN XY: 727240

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00647

Gnomad4 OTH exome AF: 0.00546

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74510

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00531

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00353 Hom.: 0

Bravo AF: 0.00288

EpiCase AF: 0.00496

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKHD1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	This variant is associated with the following publications: (PMID: 12846734) -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2020	- -

Autosomal recessive polycystic kidney disease Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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.Val1640= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs142465959) as “NA” and ClinVar (benign by Invitae and likely benign by Emory Genetics and Prevention Genetics). The RWTH AAachen University ARPKD database identified a different nucleotide change at the same position, c.4920A>C with the same protein consequence p.Val1640= as a polymorphism. The variant was identified in control databases in 619 of 277084 chromosomes at a frequency of 0.002234, seen in the following populations: European (Non-Finnish) in 521 of 126590 chromosomes (freq. 0.004116), Other in 13 of 6464 chromosomes (freq. 0.002011), Latino in 51 of 34416 chromosomes (freq. 0.001482), African in 21 of 24028 chromosomes (freq. 0.000874), Ashkenazi Jewish in 2 of 10142 chromosomes (freq. 0.0001972), South Asian in 6 of 30782 chromosomes (freq. 0.0001949), and European (Finnish) in 5 of 25792 chromosomes (freq. 0.0001939), but was not seen in the East Asian population, increasing the likelihood this could be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val1640= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.94
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142465959; hg19: chr6-51889688; COSMIC: COSV100583343;