chr6-51754962-T-C

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.8643-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,600,350 control chromosomes in the GnomAD database, including 1,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.054 ( 654 hom., cov: 32)

Exomes 𝑓: 0.012 ( 911 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.401

Publications

2 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-51754962-T-C is Benign according to our data. Variant chr6-51754962-T-C is described in ClinVar as [Benign]. Clinvar id is 262422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.8643-24A>G		intron_variant	Intron 55 of 66	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.8643-24A>G		intron_variant	Intron 55 of 66	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.8643-24A>G		intron_variant	Intron 55 of 60	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0540

AC:

8208

AN:

152074

Hom.:

651

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0602

Gnomad SAS

AF:

0.0745

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.0449

GnomAD2 exomes

AF:

0.0267

AC:

6679

AN:

250032

AF XY:

0.0254

show subpopulations

Gnomad AFR exome

AF:

0.170

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.0596

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0119

AC:

17206

AN:

1448158

Hom.:

911

Cov.:

AF XY:

0.0130

AC XY:

9350

AN XY:

721504

show subpopulations

African (AFR)

AF:

0.175

AC:

5800

AN:

33064

American (AMR)

AF:

0.0127

AC:

568

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26018

East Asian (EAS)

AF:

0.0599

AC:

2371

AN:

39606

South Asian (SAS)

AF:

0.0669

AC:

5754

AN:

85968

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.0243

AC:

139

AN:

5730

European-Non Finnish (NFE)

AF:

0.00105

AC:

1158

AN:

1099834

Other (OTH)

AF:

0.0227

AC:

1358

AN:

59888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

807

1614

2420

3227

4034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0541

AC:

8232

AN:

152192

Hom.:

654

Cov.:

AF XY:

0.0536

AC XY:

3989

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.170

AC:

7065

AN:

41510

American (AMR)

AF:

0.0197

AC:

301

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0603

AC:

312

AN:

5172

South Asian (SAS)

AF:

0.0746

AC:

359

AN:

4814

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

68016

Other (OTH)

AF:

0.0440

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

348

696

1044

1392

1740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0281

Hom.:

136

Bravo

AF:

0.0603

Asia WGS

AF:

0.0980

AC:

341

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 12, 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

-0.85

CADD

Benign

2.0

(source)

DANN

Benign

0.60

PhyloP100

-0.40

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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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chr6-51754962-T-C

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