1-152805247-T-G

Variant names:

• chr1-152805247-T-G
• rs202080650
• NM_178351.4:c.232A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178351.4(LCE1C):​c.232A>C​(p.Ser78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: LCE1C NM_178351.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.688
• Publications: 0 publications found

Genes affected

LCE1C (HGNC:29464): (late cornified envelope 1C) Predicted to be involved in keratinization. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079919994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCE1C	NM_178351.4	c.232A>C	p.Ser78Arg	missense_variant	Exon 2 of 2	ENST00000607093.2	NP_848128.1
LCE1C	NM_001276331.2	c.142A>C	p.Ser48Arg	missense_variant	Exon 3 of 3		NP_001263260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCE1C	ENST00000607093.2	c.232A>C	p.Ser78Arg	missense_variant	Exon 2 of 2	6	NM_178351.4	ENSP00000475270.1
LCE1C	ENST00000606576.1	c.142A>C	p.Ser48Arg	missense_variant	Exon 3 of 3	3		ENSP00000476034.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000919 AC: 23 AN: 250136 AF XY: 0.0000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1461652 Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 49 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.0000872 AC: 97 AN: 1112000

Other (OTH) AF: 0.0000497 AC: 3 AN: 60376

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74376

African (AFR) AF: 0.0000482 AC: 2 AN: 41508

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232A>C (p.S78R) alteration is located in exon 2 (coding exon 1) of the LCE1C gene. This alteration results from a A to C substitution at nucleotide position 232, causing the serine (S) at amino acid position 78 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	Pathogenic	0.78
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.44	T;.
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		0.69
Sift4G	Benign	0.090	T;.
Polyphen		0.78	P;.
Vest4		0.49
MutPred		0.19		Gain of MoRF binding (P = 0.0137);.;
MVP		0.32
ClinPred		0.13	T
GERP RS		2.1
Varity_R		0.81
gMVP		0.031
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs202080650; hg19: chr1-152777723; COSMIC: COSV64219307;