NM_138694.4:c.214C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_138694.4(PKHD1):c.214C>T(p.Leu72Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,794 control chromosomes in the GnomAD database, including 9,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L72L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.093 ( 708 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8388 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.398

Publications

17 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 6-52082459-G-A is Benign according to our data. Variant chr6-52082459-G-A is described in ClinVar as Benign. ClinVar VariationId is 96385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.398 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.214C>T	p.Leu72Leu	synonymous_variant	Exon 4 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.214C>T	p.Leu72Leu	synonymous_variant	Exon 4 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.214C>T	p.Leu72Leu	synonymous_variant	Exon 4 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.0926

AC:

14090

AN:

152098

Hom.:

701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0879

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.0355

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.117

GnomAD2 exomes

AF:

0.0938

AC:

23580

AN:

251360

AF XY:

0.0954

show subpopulations

Gnomad AFR exome

AF:

0.0748

Gnomad AMR exome

AF:

0.0721

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.0417

Gnomad FIN exome

AF:

0.0743

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.104

AC:

151794

AN:

1461576

Hom.:

8388

Cov.:

AF XY:

0.104

AC XY:

75485

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.0797

AC:

2669

AN:

33476

American (AMR)

AF:

0.0746

AC:

3335

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

4531

AN:

26132

East Asian (EAS)

AF:

0.0441

AC:

1750

AN:

39700

South Asian (SAS)

AF:

0.0829

AC:

7146

AN:

86248

European-Finnish (FIN)

AF:

0.0733

AC:

3917

AN:

53420

Middle Eastern (MID)

AF:

0.179

AC:

1031

AN:

5768

European-Non Finnish (NFE)

AF:

0.109

AC:

121095

AN:

1111716

Other (OTH)

AF:

0.105

AC:

6320

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

7238

14477

21715

28954

36192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4374

8748

13122

17496

21870

<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:

0.0928

AC:

14119

AN:

152218

Hom.:

708

Cov.:

AF XY:

0.0913

AC XY:

6795

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0781

AC:

3242

AN:

41536

American (AMR)

AF:

0.0879

AC:

1344

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

574

AN:

3472

East Asian (EAS)

AF:

0.0355

AC:

184

AN:

5178

South Asian (SAS)

AF:

0.0701

AC:

337

AN:

4808

European-Finnish (FIN)

AF:

0.0692

AC:

734

AN:

10604

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7324

AN:

68006

Other (OTH)

AF:

0.121

AC:

255

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

663

1325

1988

2650

3313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.109

Hom.:

1822

Bravo

AF:

0.0945

Asia WGS

AF:

0.0640

AC:

222

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.120

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKHD1, p.Leu72Leu variant was identified in 9.3% of 121382 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 4

Benign:1

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.85

(source)

DANN

Benign

0.46

PhyloP100

0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over