rs2499480

chr6-52026213-T-Cchr6-52026213-T-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.3629-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 1,595,544 control chromosomes in the GnomAD database, including 233,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17856 hom., cov: 32)
  • Exomes 𝑓: 0.54 (215935 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.291

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=-0.85).
• BP6: Variant 6-52026213-T-C is Benign according to our data. Variant chr6-52026213-T-C is described in ClinVar as [Benign]. Clinvar id is 262399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.3629-32A>G		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.3629-32A>G		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.3629-32A>G		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70544 AN: 151936 Hom.: 17854 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.518 AC: 126193 AN: 243558 Hom.: 34067 AF XY: 0.514 AC XY: 68302 AN XY: 132952

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.445

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.542 AC: 782252 AN: 1443490 Hom.: 215935 Cov.: 28 AF XY: 0.540 AC XY: 388383 AN XY: 719374

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.654

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.329

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.510

Gnomad4 NFE exome AF: 0.565

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.464 AC: 70569 AN: 152054 Hom.: 17856 Cov.: 32 AF XY: 0.461 AC XY: 34248 AN XY: 74306

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.478

Gnomad4 NFE AF: 0.560

Gnomad4 OTH AF: 0.477

Alfa AF: 0.454 Hom.: 2827

Bravo AF: 0.465

Asia WGS AF: 0.373 AC: 1301 AN: 3478

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	-0.85
Cadd	Benign	7.5
Dann	Benign	0.59

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: rs2499480; hg19: chr6-51891011; COSMIC: COSV61861258;