dbSNP rs2766125: PKHD1:c.8643-24A>G (chr6-51754962-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.0267

AC:

6679

AN:

250032

Hom.:

352

AF XY:

0.0254

AC XY:

3428

AN XY:

135184

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 SAS exome

AF:

0.0695

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

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0599

Gnomad4 SAS exome

AF:

0.0669

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.0227

GnomAD4 genome

AF:

0.0541

AC:

8232

AN:

152192

Hom.:

654

Cov.:

AF XY:

0.0536

AC XY:

3989

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.0197

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0603

Gnomad4 SAS

AF:

0.0746

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.0440

Alfa

AF:

0.0287

Hom.:

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

DANN

Benign

0.60

BranchPoint Hunter

1.0

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

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