rs750588859

Variant names:

• chr6-52084911-A-G
• rs750588859
• NM_138694.4:c.23T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_138694.4(PKHD1):​c.23T>C​(p.Leu8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,455,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 2.83
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 6-52084911-A-G is Pathogenic according to our data. Variant chr6-52084911-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528300.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 2 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.23T>C	p.Leu8Pro	missense	Exon 2 of 61	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 2 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.23T>C	p.Leu8Pro	missense	Exon 2 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251326 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1455080 Hom.: 0 Cov.: 27 AF XY: 0.0000276 AC XY: 20 AN XY: 724354

African (AFR) AF: 0.0000300 AC: 1 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000298 AC: 33 AN: 1105928

Other (OTH) AF: 0.0000665 AC: 4 AN: 60136

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive polycystic kidney disease (2)
1	1	-	Polycystic kidney disease 4 (2)
1	-	-	not provided (1)
1	-	-	PKHD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.8
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.83
MPC		0.44
ClinPred		0.91	D
GERP RS		3.8
Varity_R		0.65
gMVP		0.61
Mutation Taster		=80/20	polymorphism

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: rs750588859; hg19: chr6-51949709;