rs1326581

Variant names:

• chr6-51806363-A-G
• rs1326581
• NM_138694.4:c.8303-14990T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138694.4(PKHD1):​c.8303-14990T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 152,020 control chromosomes in the GnomAD database, including 27,559 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (27559 hom., cov: 32)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• Publications: 3 publications found

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]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8303-14990T>C		intron_variant	Intron 52 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8303-14990T>C		intron_variant	Intron 52 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8303-14990T>C		intron_variant	Intron 52 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90810 AN: 151902 Hom.: 27560 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.596

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.598 AC: 90837 AN: 152020 Hom.: 27559 Cov.: 32 AF XY: 0.603 AC XY: 44803 AN XY: 74310

African (AFR) AF: 0.506 AC: 21002 AN: 41482

American (AMR) AF: 0.675 AC: 10302 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1976 AN: 3470

East Asian (EAS) AF: 0.777 AC: 4009 AN: 5160

South Asian (SAS) AF: 0.676 AC: 3248 AN: 4808

European-Finnish (FIN) AF: 0.606 AC: 6409 AN: 10570

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 42025 AN: 67950

Other (OTH) AF: 0.591 AC: 1246 AN: 2108

Alfa AF: 0.615 Hom.: 12510

Bravo AF: 0.597

Asia WGS AF: 0.661 AC: 2299 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.2
DANN	Benign	0.79
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1326581; hg19: chr6-51671161;