NM_138694.4:c.1185T>C

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.1185T>C(p.Asp395Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,609,952 control chromosomes in the GnomAD database, including 794,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71173 hom., cov: 32)

Exomes 𝑓: 1.0 ( 723509 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.409

Publications

21 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=-0.6).

BP6

Variant 6-52059976-A-G is Benign according to our data. Variant chr6-52059976-A-G is described in CliVar as Benign. Clinvar id is 96374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52059976-A-G is described in CliVar as Benign. Clinvar id is 96374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52059976-A-G is described in CliVar as Benign. Clinvar id is 96374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52059976-A-G is described in CliVar as Benign. Clinvar id is 96374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.409 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.1185T>C	p.Asp395Asp	synonymous_variant	Exon 15 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.1185T>C	p.Asp395Asp	synonymous_variant	Exon 15 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.1185T>C	p.Asp395Asp	synonymous_variant	Exon 15 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.965

AC:

146919

AN:

152180

Hom.:

71130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.881

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.986

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.973

GnomAD2 exomes

AF:

0.990

AC:

248757

AN:

251196

AF XY:

0.993

show subpopulations

Gnomad AFR exome

AF:

0.873

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.996

AC:

1452054

AN:

1457654

Hom.:

723509

Cov.:

AF XY:

0.997

AC XY:

723137

AN XY:

725570

show subpopulations

African (AFR)

AF:

0.876

AC:

29216

AN:

33368

American (AMR)

AF:

0.992

AC:

44371

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

26066

AN:

26094

East Asian (EAS)

AF:

1.00

AC:

39680

AN:

39680

South Asian (SAS)

AF:

1.00

AC:

86137

AN:

86168

European-Finnish (FIN)

AF:

1.00

AC:

53403

AN:

53404

Middle Eastern (MID)

AF:

0.994

AC:

5721

AN:

5756

European-Non Finnish (NFE)

AF:

1.00

AC:

1107749

AN:

1108230

Other (OTH)

AF:

0.991

AC:

59711

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

259

518

776

1035

1294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21566

43132

64698

86264

107830

<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:

0.965

AC:

147020

AN:

152298

Hom.:

71173

Cov.:

AF XY:

0.967

AC XY:

72027

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.881

AC:

36566

AN:

41526

American (AMR)

AF:

0.986

AC:

15094

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

3468

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5190

AN:

5190

South Asian (SAS)

AF:

1.00

AC:

4823

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67991

AN:

68036

Other (OTH)

AF:

0.974

AC:

2058

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

233

466

698

931

1164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.983

Hom.:

38139

Bravo

AF:

0.960

Asia WGS

AF:

0.993

AC:

3454

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Benign:4

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 24, 2015

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 4

Benign:2

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

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.Asp395= variant was identified in 29 of 258 proband chromosomes (frequency: 0.11) from individuals or families with ARPKD (Rossetti 2003, Losekoot 2005, Obeidova 2015). The variant was also identified in dbSNP (ID: rs1896976) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (4x, as benign, by EGL, Counsyl, Prevention Genetics, Illumina), RWTH AAachen University ARPKD database (115x, as polymorphism) databases. The variant was not identified in LOVD 3.0, databases. The variant was also identified by our laboratory in 19 individuals with ARPKD The variant was identified in control databases in 273534 of 276906 (135258 homozygous) chromosomes at a frequency of 0.987823 The variant was identified in the following populations at a frequency greater than 1%: African in 21039 of 24008 chromosomes (freq. 0.9), other in 6413 of 6458 chromosomes (freq. 0.99), Latino in 34151 of 34410 chromosomes (freq. 0.99), European in 126382 of 126462 chromosomes (freq. 0.99), Ashkenazi Jewish in 10130 of 10142 chromosomes (freq. 0.99), Eat Asian in 18862 of 18862 chromosomes (freq. 1), Finnish in 25784 of 25784 chromosomes (freq. 1),and South Asian in 30773 of 30784 chromosomes (freq. 0.99), increasing the likelihood this a benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp395Asp variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

not provided

Benign:1

Jul 09, 2018

GeneDx

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

-0.60

CADD

Benign

5.0

(source)

DANN

Benign

0.73

PhyloP100

0.41

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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