6-31116275-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_001264.5(CDSN):c.1340C>T(p.Pro447Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
CDSN
NM_001264.5 missense
NM_001264.5 missense
Scores
2
7
8
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
CDSN (HGNC:1802): (corneodesmosin) This gene encodes a protein found in corneodesmosomes, which localize to human epidermis and other cornified squamous epithelia. The encoded protein undergoes a series of cleavages during corneocyte maturation. This gene is highly polymorphic in human populations, and variation has been associated with skin diseases such as psoriasis, hypotrichosis and peeling skin syndrome. The gene is located in the major histocompatibility complex (MHC) class I region on chromosome 6. [provided by RefSeq, Dec 2014]
PSORS1C1 (HGNC:17202): (psoriasis susceptibility 1 candidate 1) This gene is one of several genes thought to confer susceptibility to psoriasis and systemic sclerosis, located on chromosome 6 near the major histocompatibility complex (MHC) class I region. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDSN | NM_001264.5 | c.1340C>T | p.Pro447Leu | missense_variant | 2/2 | ENST00000376288.3 | |
PSORS1C1 | NM_014068.3 | c.-229+1384G>A | intron_variant | ENST00000259881.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDSN | ENST00000376288.3 | c.1340C>T | p.Pro447Leu | missense_variant | 2/2 | 1 | NM_001264.5 | P1 | |
PSORS1C1 | ENST00000259881.10 | c.-229+1384G>A | intron_variant | 1 | NM_014068.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000143 AC: 36AN: 251360Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135860
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GnomAD4 exome AF: 0.000180 AC: 263AN: 1461868Hom.: 0 Cov.: 65 AF XY: 0.000171 AC XY: 124AN XY: 727236
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2023 | The c.1340C>T (p.P447L) alteration is located in exon 2 (coding exon 2) of the CDSN gene. This alteration results from a C to T substitution at nucleotide position 1340, causing the proline (P) at amino acid position 447 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2023 | This variant is present in population databases (rs201876916, gnomAD 0.03%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1027849). This variant has not been reported in the literature in individuals affected with CDSN-related conditions. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 447 of the CDSN protein (p.Pro447Leu). - |
Hypotrichosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 07, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at