Genetic Variant LCE1C:p.Ser63Gly (chr1-152805292-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178351.4(LCE1C):c.187A>G(p.Ser63Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LCE1C
NM_178351.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.629

Publications

0 publications found

Variant links:

Genes affected

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

LCE1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066708416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCE1C	NM_178351.4 link	c.187A>G	p.Ser63Gly	missense_variant	Exon 2 of 2	ENST00000607093.2	NP_848128.1	Q5T751
LCE1C	NM_001276331.2 link	c.97A>G	p.Ser33Gly	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 link	c.187A>G	p.Ser63Gly	missense_variant	Exon 2 of 2	6	NM_178351.4	ENSP00000475270.1		Q5T751
LCE1C	ENST00000606576.1 link	c.97A>G	p.Ser33Gly	missense_variant	Exon 3 of 3	3		ENSP00000476034.1		U3KQM4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151890

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250656

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41352

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.187A>G (p.S63G) alteration is located in exon 2 (coding exon 1) of the LCE1C gene. This alteration results from a A to G substitution at nucleotide position 187, causing the serine (S) at amino acid position 63 to be replaced by a glycine (G). 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

0.083

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0060

T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.39

T;.

M_CAP

Benign

0.022

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.43

N;.

PhyloP100

0.63

Sift4G

Benign

0.17

T;.

Polyphen

0.0

B;.

Vest4

0.18

MutPred

0.11

Loss of phosphorylation at S63 (P = 0.0036);.;

MVP

0.14

ClinPred

0.041

GERP RS

1.8

Varity_R

0.35

gMVP

0.018

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over