rs3920621

chr6-51775953-C-G

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.8441-32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 984,000 control chromosomes in the GnomAD database, including 91,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11127 hom., cov: 32)
  • Exomes 𝑓: 0.43 (80321 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.770

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 (BayesDel_noAF=-0.81).
• BP6: Variant 6-51775953-C-G is Benign according to our data. Variant chr6-51775953-C-G is described in ClinVar as [Benign]. Clinvar id is 262421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.8441-32G>C		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.8441-32G>C		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.8441-32G>C		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52305 AN: 151508 Hom.: 11132 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.345

GnomAD3 exomes AF: 0.445 AC: 107151 AN: 240598 Hom.: 26225 AF XY: 0.449 AC XY: 58600 AN XY: 130612

Gnomad AFR exome AF: 0.0935

Gnomad AMR exome AF: 0.589

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.704

Gnomad SAS exome AF: 0.520

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.428 AC: 356043 AN: 832374 Hom.: 80321 Cov.: 11 AF XY: 0.432 AC XY: 189971 AN XY: 440000

Gnomad4 AFR exome AF: 0.0913

Gnomad4 AMR exome AF: 0.571

Gnomad4 ASJ exome AF: 0.318

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.521

Gnomad4 FIN exome AF: 0.435

Gnomad4 NFE exome AF: 0.410

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.345 AC: 52290 AN: 151626 Hom.: 11127 Cov.: 32 AF XY: 0.355 AC XY: 26282 AN XY: 74062

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.674

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.413

Gnomad4 OTH AF: 0.341

Alfa AF: 0.373 Hom.: 2118

Bravo AF: 0.334

Asia WGS AF: 0.506 AC: 1754 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 12, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.30
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3920621; hg19: chr6-51640751; COSMIC: COSV61879949;