rs201017366

Positions:

• chr6-51855874-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.7911+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,583,284 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.29

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-51855874-A-G is Benign according to our data. Variant chr6-51855874-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554778.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.7911+19T>C		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.7911+19T>C		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.7911+19T>C		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000497 AC: 125 AN: 251320 Hom.: 1 AF XY: 0.000515 AC XY: 70 AN XY: 135818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000331 AC: 474 AN: 1430962 Hom.: 2 Cov.: 26 AF XY: 0.000354 AC XY: 253 AN XY: 713826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.000742

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74488

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.000355

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 08, 2019

Variant summary: PKHD1 c.7911+19T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0005 in 251520 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.0005 vs 0.0071), allowing no conclusion about variant significance. c.7911+19T>C has been reported in the literature in at least one individual affected with Polycystic Kidney and Hepatic Disease (Sharp_2005). This report does not provide unequivocal conclusions about association of the variant with Polycystic Kidney and Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.8
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs201017366; hg19: chr6-51720672;