6-51868009-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_138694.4(PKHD1):c.7587G>A(p.Gly2529Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,611,260 control chromosomes in the GnomAD database, including 284,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2529G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.50 ( 20786 hom., cov: 32)

Exomes 𝑓: 0.59 ( 263279 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.43

Publications

25 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 6-51868009-C-T is Benign according to our data. Variant chr6-51868009-C-T is described in ClinVar as Benign. ClinVar VariationId is 96421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.7587G>A	p.Gly2529Gly	synonymous	Exon 48 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.7587G>A	p.Gly2529Gly	synonymous	Exon 48 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.7587G>A	p.Gly2529Gly	synonymous	Exon 48 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.7587G>A	p.Gly2529Gly	synonymous	Exon 48 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.501

AC:

76144

AN:

151858

Hom.:

20777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.787

Gnomad AMR

AF:

0.416

Gnomad ASJ

AF:

0.710

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.680

Gnomad NFE

AF:

0.632

Gnomad OTH

AF:

0.555

GnomAD2 exomes

AF:

0.499

AC:

124905

AN:

250528

AF XY:

0.511

show subpopulations

Gnomad AFR exome

AF:

0.339

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.712

Gnomad EAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.494

Gnomad NFE exome

AF:

0.633

Gnomad OTH exome

AF:

0.579

GnomAD4 exome

AF:

0.589

AC:

859478

AN:

1459284

Hom.:

263279

Cov.:

AF XY:

0.587

AC XY:

426066

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.352

AC:

11767

AN:

33424

American (AMR)

AF:

0.331

AC:

14786

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.714

AC:

18638

AN:

26098

East Asian (EAS)

AF:

0.166

AC:

6569

AN:

39686

South Asian (SAS)

AF:

0.440

AC:

37907

AN:

86210

European-Finnish (FIN)

AF:

0.510

AC:

27235

AN:

53352

Middle Eastern (MID)

AF:

0.699

AC:

4025

AN:

5760

European-Non Finnish (NFE)

AF:

0.634

AC:

703662

AN:

1109770

Other (OTH)

AF:

0.578

AC:

34889

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

16872

33743

50615

67486

84358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18330

36660

54990

73320

91650

<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:

0.501

AC:

76177

AN:

151976

Hom.:

20786

Cov.:

AF XY:

0.488

AC XY:

36264

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.350

AC:

14497

AN:

41442

American (AMR)

AF:

0.415

AC:

6331

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.710

AC:

2463

AN:

3470

East Asian (EAS)

AF:

0.136

AC:

705

AN:

5180

South Asian (SAS)

AF:

0.415

AC:

2001

AN:

4816

European-Finnish (FIN)

AF:

0.490

AC:

5178

AN:

10564

Middle Eastern (MID)

AF:

0.677

AC:

199

AN:

294

European-Non Finnish (NFE)

AF:

0.632

AC:

42912

AN:

67942

Other (OTH)

AF:

0.555

AC:

1173

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1804

3609

5413

7218

9022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.582

Hom.:

79043

Bravo

AF:

0.490

Asia WGS

AF:

0.320

AC:

1114

AN:

3478

EpiCase

AF:

0.647

EpiControl

AF:

0.637

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive polycystic kidney disease (3)

not provided (2)

not specified (2)

Polycystic kidney disease 4 (2)

Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

4.4

(source)

DANN

Benign

0.63

PhyloP100

-1.4

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over