NM_138694.4:c.8173+37G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.8173+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,346,820 control chromosomes in the GnomAD database, including 2,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 231 hom., cov: 32)

Exomes 𝑓: 0.051 ( 1816 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.454

Publications

6 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 -20 ACMG points.

BP4

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

BP6

Variant 6-51836367-C-T is Benign according to our data. Variant chr6-51836367-C-T is described in ClinVar as Benign. ClinVar VariationId is 262419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.8173+37G>A		intron_variant	Intron 51 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.8173+37G>A		intron_variant	Intron 51 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.8173+37G>A		intron_variant	Intron 51 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.0537

AC:

8166

AN:

152014

Hom.:

228

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0653

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0365

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.0515

Gnomad SAS

AF:

0.0747

Gnomad FIN

AF:

0.0566

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0509

Gnomad OTH

AF:

0.0449

GnomAD2 exomes

AF:

0.0517

AC:

12968

AN:

250844

AF XY:

0.0519

show subpopulations

Gnomad AFR exome

AF:

0.0657

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.0320

Gnomad EAS exome

AF:

0.0327

Gnomad FIN exome

AF:

0.0575

Gnomad NFE exome

AF:

0.0497

Gnomad OTH exome

AF:

0.0595

GnomAD4 exome

AF:

0.0507

AC:

60580

AN:

1194690

Hom.:

1816

Cov.:

AF XY:

0.0515

AC XY:

31321

AN XY:

607924

show subpopulations

African (AFR)

AF:

0.0672

AC:

1892

AN:

28160

American (AMR)

AF:

0.0405

AC:

1799

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.0335

AC:

819

AN:

24450

East Asian (EAS)

AF:

0.0848

AC:

3259

AN:

38422

South Asian (SAS)

AF:

0.0733

AC:

5945

AN:

81074

European-Finnish (FIN)

AF:

0.0561

AC:

2988

AN:

53254

Middle Eastern (MID)

AF:

0.0316

AC:

167

AN:

5284

European-Non Finnish (NFE)

AF:

0.0475

AC:

41207

AN:

868134

Other (OTH)

AF:

0.0486

AC:

2504

AN:

51540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2959

5918

8876

11835

14794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1352

2704

4056

5408

6760

<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:

0.0539

AC:

8195

AN:

152130

Hom.:

231

Cov.:

AF XY:

0.0540

AC XY:

4017

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0655

AC:

2720

AN:

41506

American (AMR)

AF:

0.0365

AC:

558

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3468

East Asian (EAS)

AF:

0.0520

AC:

269

AN:

5170

South Asian (SAS)

AF:

0.0745

AC:

359

AN:

4818

European-Finnish (FIN)

AF:

0.0566

AC:

599

AN:

10580

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0509

AC:

3462

AN:

67984

Other (OTH)

AF:

0.0478

AC:

101

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

402

805

1207

1610

2012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0533

Hom.:

378

Bravo

AF:

0.0514

Asia WGS

AF:

0.0990

AC:

343

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive polycystic kidney disease

Benign:1

Apr 13, 2018

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

-0.88

CADD

Benign

1.3

(source)

DANN

Benign

0.64

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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