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GeneBe

13-77556623-C-G

Variant summary

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

The NM_144777.3(SCEL):c.71C>G(p.Thr24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SCEL
NM_144777.3 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.243
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=0.04655075).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCELNM_144777.3 linkuse as main transcriptc.71C>G p.Thr24Arg missense_variant 3/33 ENST00000349847.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCELENST00000349847.4 linkuse as main transcriptc.71C>G p.Thr24Arg missense_variant 3/331 NM_144777.3 P2O95171-1
SCELENST00000377246.7 linkuse as main transcriptc.71C>G p.Thr24Arg missense_variant 3/321 A2O95171-2
SCELENST00000535157.5 linkuse as main transcriptc.71C>G p.Thr24Arg missense_variant 3/312 A2O95171-3
SCELENST00000471491.5 linkuse as main transcriptc.71C>G p.Thr24Arg missense_variant, NMD_transcript_variant 3/192

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000676
AC:
17
AN:
251326
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000463
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1461700
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000492
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:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000494
AC:
6

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 GeneticsJan 25, 2023The c.71C>G (p.T24R) alteration is located in exon 3 (coding exon 2) of the SCEL gene. This alteration results from a C to G substitution at nucleotide position 71, causing the threonine (T) at amino acid position 24 to be replaced by an arginine (R). 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
0.091
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.62
Cadd
Benign
1.6
Dann
Benign
0.89
Eigen
Benign
-0.95
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.65
T;T;T
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.047
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;L;L
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.6
N;N;N
REVEL
Benign
0.063
Sift
Uncertain
0.010
D;D;D
Sift4G
Benign
0.11
T;T;T
Polyphen
0.65
.;P;P
Vest4
0.26
MutPred
0.16
Loss of phosphorylation at T24 (P = 0.0277);Loss of phosphorylation at T24 (P = 0.0277);Loss of phosphorylation at T24 (P = 0.0277);
MVP
0.13
MPC
0.058
ClinPred
0.070
T
GERP RS
-0.15
Varity_R
0.10
gMVP
0.064

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs749131306; hg19: chr13-78130758; API