Genetic Variant PKHD1:c.*2553dupA (chr6-51616527-A-AT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_138694.4(PKHD1):c.*2553dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 357,738 control chromosomes in the GnomAD database, including 658 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.10 ( 653 hom., cov: 28)

Exomes 𝑓: 0.12 ( 5 hom. )

Consequence

PKHD1
NM_138694.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0790

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 links:

ENSG00000228689 (HGNC:):

ENSG00000228689 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.*2553dupA		3_prime_UTR_variant	Exon 67 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKHD1	ENST00000371117 link	c.*2553dupA	3_prime_UTR_variant	Exon 67 of 67	1	NM_138694.4	ENSP00000360158.3	P08F94-1
ENSG00000228689	ENST00000454361.1 link	n.81-5813dupT	intron_variant	Intron 1 of 1	3
ENSG00000228689	ENST00000589278.6 link	n.811-5818dupT	intron_variant	Intron 2 of 2	5
ENSG00000228689	ENST00000650088.1 link	n.222-5813dupT	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

14152

AN:

141108

Hom.:

654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0977

Gnomad AMR

AF:

0.0804

Gnomad ASJ

AF:

0.0933

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.0912

Gnomad FIN

AF:

0.0967

Gnomad MID

AF:

0.0331

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0871

GnomAD4 exome

AF:

0.118

AC:

25656

AN:

216580

Hom.:

Cov.:

AF XY:

0.118

AC XY:

12983

AN XY:

110112

show subpopulations

Gnomad4 AFR exome

AF:

0.114

AC:

724

AN:

6344

Gnomad4 AMR exome

AF:

0.105

AC:

690

AN:

6598

Gnomad4 ASJ exome

AF:

0.117

AC:

952

AN:

8130

Gnomad4 EAS exome

AF:

0.168

AC:

3472

AN:

20682

Gnomad4 SAS exome

AF:

0.0932

AC:

189

AN:

2028

Gnomad4 FIN exome

AF:

0.118

AC:

2108

AN:

17896

Gnomad4 NFE exome

AF:

0.113

AC:

15733

AN:

139448

Gnomad4 Remaining exome

AF:

0.118

AC:

1689

AN:

14344

Heterozygous variant carriers

1310

2620

3930

5240

6550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

104

208

312

416

520

<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:

0.100

AC:

14167

AN:

141158

Hom.:

653

Cov.:

AF XY:

0.0984

AC XY:

6724

AN XY:

68340

show subpopulations

Gnomad4 AFR

AF:

0.101

AC:

0.100888

AN:

0.100888

Gnomad4 AMR

AF:

0.0803

AC:

0.0802654

AN:

0.0802654

Gnomad4 ASJ

AF:

0.0933

AC:

0.0933333

AN:

0.0933333

Gnomad4 EAS

AF:

0.170

AC:

0.170431

AN:

0.170431

Gnomad4 SAS

AF:

0.0914

AC:

0.0913929

AN:

0.0913929

Gnomad4 FIN

AF:

0.0967

AC:

0.0966667

AN:

0.0966667

Gnomad4 NFE

AF:

0.101

AC:

0.101289

AN:

0.101289

Gnomad4 OTH

AF:

0.0874

AC:

0.0874089

AN:

0.0874089

Heterozygous variant carriers

619

1238

1857

2476

3095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0263

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over