chr6-51855874-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138694.4(PKHD1):​c.7911+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,583,284 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 6-51855874-A-G is Benign according to our data. Variant chr6-51855874-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554778.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKHD1NM_138694.4 linkc.7911+19T>C intron_variant Intron 49 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.7911+19T>C intron_variant Intron 49 of 66 1 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkc.7911+19T>C intron_variant Intron 49 of 60 5 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000851
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000497
AC:
125
AN:
251320
Hom.:
1
AF XY:
0.000515
AC XY:
70
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000578
Gnomad ASJ exome
AF:
0.00198
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000359
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000581
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.000331
AC:
474
AN:
1430962
Hom.:
2
Cov.:
26
AF XY:
0.000354
AC XY:
253
AN XY:
713826
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000537
Gnomad4 ASJ exome
AF:
0.00201
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000304
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000284
Gnomad4 OTH exome
AF:
0.000742
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.000349
AC XY:
26
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000850
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000603
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000854
Hom.:
0
Bravo
AF:
0.000355
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1Benign:1
Dec 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 02, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Jan 09, 2025
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.7911+19T>C alters a conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation 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 0.00033 in 1576366 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not higher than the maximum estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0071). The variant, c.7911+19T>C, has been reported in the literature in individuals affected with polycystic kidney disease (e.g. Sharp_2005, Nigro_2023), however, no supportive evidence for causality was provided. These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15805161, 37372416). ClinVar contains an entry for this variant (Variation ID: 554778). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
7.8
DANN
Benign
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs201017366; hg19: chr6-51720672; API