13-77613943-A-C

Position:

• chr13-77613943-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144777.3(SCEL):​c.1439A>C​(p.Lys480Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K480R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCEL NM_144777.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2019059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCEL	NM_144777.3	c.1439A>C	p.Lys480Thr	missense_variant	24/33	ENST00000349847.4	NP_659001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCEL	ENST00000349847.4	c.1439A>C	p.Lys480Thr	missense_variant	24/33	1	NM_144777.3	ENSP00000302579	P2
SCEL	ENST00000377246.7	c.1379A>C	p.Lys460Thr	missense_variant	23/32	1		ENSP00000366454	A2
SCEL	ENST00000535157.5	c.1313A>C	p.Lys438Thr	missense_variant	22/31	2		ENSP00000437895	A2
SCEL	ENST00000469982.1	n.535A>C		non_coding_transcript_exon_variant	9/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	.;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	2.0	.;.;M
MutationTaster	Benign	0.95	P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.065	T;T;T
Sift4G	Benign	0.31	T;D;T
Polyphen		0.45, 0.29	.;B;B
Vest4		0.24
MutPred		0.28		.;.;Gain of catalytic residue at N481 (P = 0.011);
MVP		0.76
MPC		0.13
ClinPred		0.50	D
GERP RS		3.9
Varity_R		0.069
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs8002725; hg19: chr13-78188078;