chr7-47846960-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_138295.5(PKD1L1):​c.5072G>C​(p.Cys1691Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PKD1L1
NM_138295.5 missense

Scores

8
8
3

Clinical Significance

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

Conservation

PhyloP100: 4.80

Publications

3 publications found
Variant links:
Genes affected
PKD1L1 (HGNC:18053): (polycystin 1 like 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family containing 11 transmembrane domains, a receptor for egg jelly (REJ) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. The encoded protein may play a role in the male reproductive system. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]
PKD1L1 Gene-Disease associations (from GenCC):
  • heterotaxy, visceral, 8, autosomal
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
  • situs inversus
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.944
PP5
Variant 7-47846960-C-G is Pathogenic according to our data. Variant chr7-47846960-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235198.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKD1L1NM_138295.5 linkc.5072G>C p.Cys1691Ser missense_variant Exon 32 of 57 ENST00000289672.7 NP_612152.1
PKD1L1XM_017011798.3 linkc.5249G>C p.Cys1750Ser missense_variant Exon 33 of 59 XP_016867287.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKD1L1ENST00000289672.7 linkc.5072G>C p.Cys1691Ser missense_variant Exon 32 of 57 1 NM_138295.5 ENSP00000289672.2 Q8TDX9-1
PKD1L1ENST00000690269.1 linkc.5072G>C p.Cys1691Ser missense_variant Exon 32 of 58 ENSP00000510743.1 A0A8I5KWV8
PKD1L1ENST00000685709.1 linkc.4904G>C p.Cys1635Ser missense_variant Exon 31 of 56 ENSP00000509540.1 A0A8I5QKU1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461672
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727122
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44692
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86180
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000135
AC:
15
AN:
1111918
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5208
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Situs inversus Pathogenic:1
May 27, 2016
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

Pathogenicity based on finding the variant in the homozygous state in a female with situs inversus totalis and congenital heart defect. -

Heterotaxy, visceral, 8, autosomal Pathogenic:1
Dec 14, 2016
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Inborn genetic diseases Uncertain:1
Mar 04, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.5072G>C (p.C1691S) alteration is located in exon 32 (coding exon 32) of the PKD1L1 gene. This alteration results from a G to C substitution at nucleotide position 5072, causing the cysteine (C) at amino acid position 1691 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in the homozygous state and/or in conjunction with other PKD1L1 variant(s) in individual(s) with features consistent with PKD1L1-related visceral heterotaxy (Vetrini, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.66
D
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.46
T
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
0.078
D
MutationAssessor
Uncertain
2.5
M
PhyloP100
4.8
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-9.3
D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.75
Loss of sheet (P = 0.0104);
MVP
0.85
MPC
0.54
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.93
gMVP
0.66
Mutation Taster
=27/73
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs886037834; hg19: chr7-47886558; API