6-51856089-GA-GAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_138694.4(PKHD1):c.7734-21_7734-20dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,448,334 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.207

Publications

0 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.

BP6

Variant 6-51856089-G-GAA is Benign according to our data. Variant chr6-51856089-G-GAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1050840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.7734-21_7734-20dupTT		intron_variant	Intron 48 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.7734-20_7734-19insTT		intron_variant	Intron 48 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.7734-20_7734-19insTT		intron_variant	Intron 48 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.000830

AC:

126

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00104

AC:

257

AN:

246858

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000680

Gnomad ASJ exome

AF:

0.00121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.00121

AC:

1568

AN:

1296444

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

808

AN XY:

654098

show subpopulations

African (AFR)

AF:

0.000203

AC:

AN:

29524

American (AMR)

AF:

0.000712

AC:

AN:

43564

Ashkenazi Jewish (ASJ)

AF:

0.00108

AC:

AN:

25056

East Asian (EAS)

AF:

0.00

AC:

AN:

38122

South Asian (SAS)

AF:

0.000441

AC:

AN:

81590

European-Finnish (FIN)

AF:

0.000132

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.00143

AC:

1384

AN:

965550

Other (OTH)

AF:

0.00110

AC:

AN:

54442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.000823

AC:

125

AN:

151890

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41454

American (AMR)

AF:

0.000720

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

67904

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000584

Hom.:

Bravo

AF:

0.000914

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 21, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKHD1 c.7734-21_7734-20dupTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.001 in 246858 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.001 vs 0.0071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7734-21_7734-20dupTT in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. One locus specific database reports a likely benign outcome. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive polycystic kidney disease

Benign:1

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 4

Benign:1

Aug 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over