Genetic Variant PKHD1:c.6122-2264T>C (chr6-51914840-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138694.4(PKHD1):c.6122-2264T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 151,858 control chromosomes in the GnomAD database, including 19,908 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 19908 hom., cov: 32)

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.656

Publications

5 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.6122-2264T>C		intron_variant	Intron 37 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.6122-2264T>C		intron_variant	Intron 37 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.6122-2264T>C		intron_variant	Intron 37 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

74335

AN:

151740

Hom.:

19870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.641

Gnomad AMI

AF:

0.213

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.867

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.517

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.355

Gnomad OTH

AF:

0.435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.490

AC:

74421

AN:

151858

Hom.:

19908

Cov.:

AF XY:

0.505

AC XY:

37441

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.641

AC:

26576

AN:

41448

American (AMR)

AF:

0.576

AC:

8769

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1010

AN:

3468

East Asian (EAS)

AF:

0.867

AC:

4458

AN:

5140

South Asian (SAS)

AF:

0.591

AC:

2848

AN:

4820

European-Finnish (FIN)

AF:

0.517

AC:

5450

AN:

10540

Middle Eastern (MID)

AF:

0.329

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.355

AC:

24104

AN:

67904

Other (OTH)

AF:

0.435

AC:

916

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1793

3587

5380

7174

8967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.389

Hom.:

6458

Bravo

AF:

0.500

Asia WGS

AF:

0.685

AC:

2380

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.046

(source)

DANN

Benign

0.30

PhyloP100

-0.66

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over