chr6-52073547-TGAA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):​c.449-9_449-7delTTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,555,584 control chromosomes in the GnomAD database, including 6 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 3 hom. )

Consequence

PKHD1
NM_138694.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.81
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 6-52073547-TGAA-T is Benign according to our data. Variant chr6-52073547-TGAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 198616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00284 (433/152314) while in subpopulation AFR AF= 0.0101 (420/41570). AF 95% confidence interval is 0.00931. There are 3 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKHD1NM_138694.4 linkc.449-9_449-7delTTC splice_region_variant, intron_variant Intron 6 of 66 ENST00000371117.8 NP_619639.3 P08F94-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKHD1ENST00000371117.8 linkc.449-9_449-7delTTC splice_region_variant, intron_variant Intron 6 of 66 1 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkc.449-9_449-7delTTC splice_region_variant, intron_variant Intron 6 of 60 5 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.00284
AC:
432
AN:
152196
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0101
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000785
AC:
197
AN:
250928
Hom.:
2
AF XY:
0.000649
AC XY:
88
AN XY:
135616
show subpopulations
Gnomad AFR exome
AF:
0.0106
Gnomad AMR exome
AF:
0.000637
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000274
AC:
384
AN:
1403270
Hom.:
3
AF XY:
0.000231
AC XY:
162
AN XY:
701954
show subpopulations
Gnomad4 AFR exome
AF:
0.0100
Gnomad4 AMR exome
AF:
0.000650
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000283
Gnomad4 OTH exome
AF:
0.000446
GnomAD4 genome
AF:
0.00284
AC:
433
AN:
152314
Hom.:
3
Cov.:
32
AF XY:
0.00275
AC XY:
205
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0101
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.00135
Hom.:
0
Bravo
AF:
0.00338
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Dec 02, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 12, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PKHD1 c.449-9_449-7delTTC 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. The variant allele was found at a frequency of 0.00096 in 121106 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.449-9_449-7delTTC in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Autosomal recessive polycystic kidney disease Benign:2
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 15, 2017
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:1
Mar 09, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PKHD1-related disorder Benign:1
Dec 20, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Polycystic kidney disease 4 Benign:1
Aug 03, 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

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs545812620; hg19: chr6-51938345; API