NM_138694.4:c.7744C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_138694.4(PKHD1):c.7744C>T(p.Pro2582Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,599,152 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00062 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 2.44

Publications

4 publications found

Variant links:

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

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_138694.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0052398443).

BP6

Variant 6-51856060-G-A is Benign according to our data. Variant chr6-51856060-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288719.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.7744C>T	p.Pro2582Ser	missense	Exon 49 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.7744C>T	p.Pro2582Ser	missense	Exon 49 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.7744C>T	p.Pro2582Ser	missense	Exon 49 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.7744C>T	p.Pro2582Ser	missense	Exon 49 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000764

AC:

192

AN:

251324

AF XY:

0.000670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000390

AC:

564

AN:

1446886

Hom.:

Cov.:

AF XY:

0.000365

AC XY:

263

AN XY:

720932

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33062

American (AMR)

AF:

0.00123

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

307

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39422

South Asian (SAS)

AF:

0.000210

AC:

AN:

85722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00818

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

1098988

Other (OTH)

AF:

0.00124

AC:

AN:

59790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000617

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41546

American (AMR)

AF:

0.00196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000742

Hom.:

Bravo

AF:

0.000801

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive polycystic kidney disease (3)

not provided (2)

Autosomal dominant polycystic liver disease (1)

not specified (1)

PKHD1-related disorder (1)

Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.081

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.78

M_CAP

Benign

0.063

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.8

PhyloP100

2.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

REVEL

Benign

0.26

Sift

Benign

0.99

Sift4G

Benign

0.11

Polyphen

0.98

Vest4

0.20

MVP

0.90

MPC

0.083

ClinPred

0.051

GERP RS

4.4

Varity_R

0.031

gMVP

0.69

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over