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GeneBe

13-77555907-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144777.3(SCEL):c.32C>T(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,406 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

SCEL
NM_144777.3 missense

Scores

7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.568
Variant links:
Genes affected
SCEL (HGNC:10573): (sciellin) The protein encoded by this gene is a precursor to the cornified envelope of terminally differentiated keratinocytes. This protein localizes to the periphery of cells and may function in the assembly or regulation of proteins in the cornified envelope. Transcript variants encoding different isoforms exist. A transcript variant utilizing an alternative polyA signal has been described in the literature, but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.014837921).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCELNM_144777.3 linkuse as main transcriptc.32C>T p.Pro11Leu missense_variant 2/33 ENST00000349847.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCELENST00000349847.4 linkuse as main transcriptc.32C>T p.Pro11Leu missense_variant 2/331 NM_144777.3 P2O95171-1
SCELENST00000377246.7 linkuse as main transcriptc.32C>T p.Pro11Leu missense_variant 2/321 A2O95171-2
SCELENST00000535157.5 linkuse as main transcriptc.32C>T p.Pro11Leu missense_variant 2/312 A2O95171-3
SCELENST00000471491.5 linkuse as main transcriptc.32C>T p.Pro11Leu missense_variant, NMD_transcript_variant 2/192

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152116
Hom.:
0
Cov.:
32
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:
0.000772
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251104
Hom.:
0
AF XY:
0.0000884
AC XY:
12
AN XY:
135698
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00163
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461172
Hom.:
1
Cov.:
29
AF XY:
0.0000468
AC XY:
34
AN XY:
726930
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00156
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000774
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000529
ExAC
AF:
0.0000988
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 28, 2023The c.32C>T (p.P11L) alteration is located in exon 2 (coding exon 1) of the SCEL gene. This alteration results from a C to T substitution at nucleotide position 32, causing the proline (P) at amino acid position 11 to be replaced by a leucine (L). 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
Benign
0.11
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.51
Cadd
Benign
21
Dann
Uncertain
1.0
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.27
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.015
T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
1.5
L;L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-4.3
D;D;D
REVEL
Benign
0.15
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.10
MVP
0.32
MPC
0.057
ClinPred
0.25
T
GERP RS
5.5
Varity_R
0.12
gMVP
0.078

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: rs140695935; hg19: chr13-78130042; COSMIC: COSV62993041; API