Genetic Variant NM_014357.5:c.74C>T (chr1-152686917-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014357.5(LCE2B):c.74C>T(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 1 hom. )

Consequence

LCE2B
NM_014357.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.799

Publications

0 publications found

Variant links:

Genes affected

LCE2B (HGNC:16610): (late cornified envelope 2B) This gene is one of the at least 20 genes expressed during epidermal differentiation and located on chromosomal band 1q21. This gene is involved in epidermal differentiation, and it is expressed at high levels in normal and psoriatic skin, but not in cultured keratinocytes or in any other tested cell types or tissues. [provided by RefSeq, Jul 2008]

LCE2B links:

ENSG00000304363 (HGNC:):

ENSG00000304363 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030427635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCE2B	NM_014357.5 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 2 of 2	ENST00000368780.4	NP_055172.1	O14633

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LCE2B	ENST00000368780.4 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 2 of 2	1	NM_014357.5	ENSP00000357769.3	O14633
ENSG00000304363	ENST00000802896.1 link	n.81-8400G>A		intron_variant	Intron 1 of 3
ENSG00000304363	ENST00000802897.1 link	n.69-20191G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000600

AC:

151

AN:

251468

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000889

AC:

1299

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000875

AC XY:

636

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000636

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00107

AC:

1194

AN:

1112010

Other (OTH)

AF:

0.000795

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000486

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41558

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000623

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000823

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000958

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000544

AC:

EpiCase

AF:

0.00142

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.74C>T (p.P25L) alteration is located in exon 2 (coding exon 1) of the LCE2B gene. This alteration results from a C to T substitution at nucleotide position 74, causing the proline (P) at amino acid position 25 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

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.19

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.42

M_CAP

Benign

0.0010

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

0.80

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.064

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

0.85

Vest4

0.28

MVP

0.23

MPC

0.0028

ClinPred

0.13

GERP RS

2.5

Varity_R

0.065

gMVP

0.038

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over