rs76012218

chr6-52065043-T-Achr6-52065043-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138694.4(PKHD1):c.888A>T(p.Pro296=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,581,134 control chromosomes in the GnomAD database, including 33 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. P296P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0086 (22 hom., cov: 23)
  • Exomes 𝑓: 0.00091 (11 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.102

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 6-52065043-T-A is Benign according to our data. Variant chr6-52065043-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 220081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52065043-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00857 (1249/145674) while in subpopulation AFR AF= 0.0299 (1156/38656). AF 95% confidence interval is 0.0285. There are 22 homozygotes in gnomad4. There are 609 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.888A>T	p.Pro296=	synonymous_variant	13/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.888A>T	p.Pro296=	synonymous_variant	13/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.888A>T	p.Pro296=	synonymous_variant	13/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1244 AN: 145596 Hom.: 22 Cov.: 23

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00443

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00604

GnomAD3 exomes AF: 0.00239 AC: 600 AN: 250654 Hom.: 7 AF XY: 0.00194 AC XY: 263 AN XY: 135490

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000911 AC: 1308 AN: 1435460 Hom.: 11 Cov.: 28 AF XY: 0.000811 AC XY: 580 AN XY: 715048

Gnomad4 AFR exome AF: 0.0295

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000100

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00857 AC: 1249 AN: 145674 Hom.: 22 Cov.: 23 AF XY: 0.00861 AC XY: 609 AN XY: 70742

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00443

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000223

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00599

Alfa AF: 0.00158 Hom.: 1

Bravo AF: 0.0101

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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.Pro296= 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: rs76012218) as With Benign allele, ClinVar (classified as benign by Invitae and Prevention Genetics), RWTH AAachen University ARPKD, databases. The variant was identified in control databases in 809 of 274254 chromosomes (13 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 717 of 23442 chromosomes (freq: 0.03), Other in 13 of 6372 chromosomes (freq: 0.002), Latino in 57 of 34292 chromosomes (freq: 0.002), European in 19 of 125570 chromosomes (freq: 0.0002), Ashkenazi Jewish in 2 of 10134 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, Finnish, populations. The p.Pro296= 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	4.0
Dann	Benign	0.68

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: rs76012218; hg19: chr6-51929841; COSMIC: COSV61881172;