6-51808641-C-T

Variant names:

• chr6-51808641-C-T
• rs9296661
• NM_138694.4:c.8303-17268G>A

Variant summary

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

The NM_138694.4(PKHD1):​c.8303-17268G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 151,790 control chromosomes in the GnomAD database, including 24,783 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 0.57 (24783 hom., cov: 31)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• Publications: 13 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.8303-17268G>A		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8303-17268G>A		intron	N/A	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8303-17268G>A		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.8303-17268G>A		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86062 AN: 151672 Hom.: 24784 Cov.: 31

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.554

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

GnomAD4 genome AF: 0.567 AC: 86088 AN: 151790 Hom.: 24783 Cov.: 31 AF XY: 0.574 AC XY: 42612 AN XY: 74176

African (AFR) AF: 0.498 AC: 20643 AN: 41428

American (AMR) AF: 0.639 AC: 9733 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1759 AN: 3466

East Asian (EAS) AF: 0.775 AC: 4002 AN: 5164

South Asian (SAS) AF: 0.667 AC: 3209 AN: 4814

European-Finnish (FIN) AF: 0.591 AC: 6223 AN: 10530

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38776 AN: 67860

Other (OTH) AF: 0.550 AC: 1155 AN: 2100

Alfa AF: 0.568 Hom.: 36281

Bravo AF: 0.565

Asia WGS AF: 0.656 AC: 2278 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.3
DANN	Benign	0.55
PhyloP100		-0.18
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: rs9296661; hg19: chr6-51673439;