Genetic Variant LORICRIN:p.Cys16Arg (chr1-153260995-T-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000427.3(LORICRIN):c.46T>C(p.Cys16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,592,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

LORICRIN
NM_000427.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

Variant links:

Genes affected

LORICRIN (HGNC:6663): (loricrin cornified envelope precursor protein) This gene encodes loricrin, a major protein component of the cornified cell envelope found in terminally differentiated epidermal cells. Mutations in this gene are associated with Vohwinkel's syndrome and progressive symmetric erythrokeratoderma, both inherited skin diseases. [provided by RefSeq, Jul 2008]

LORICRIN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BS2

High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LORICRIN	NM_000427.3 link	c.46T>C	p.Cys16Arg	missense_variant	Exon 2 of 2	ENST00000368742.4	NP_000418.2	P23490

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LORICRIN	ENST00000368742.4 link	c.46T>C	p.Cys16Arg	missense_variant	Exon 2 of 2	1	NM_000427.3	ENSP00000357731.3		P23490

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.000206

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

216226

Hom.:

AF XY:

0.0000671

AC XY:

AN XY:

119306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000331

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:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

204

AN:

1440232

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

716306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000235

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:

0.000168

Gnomad4 OTH exome

AF:

0.000302

GnomAD4 genome

AF:

0.000112

AC:

AN:

151846

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46T>C (p.C16R) alteration is located in exon 2 (coding exon 1) of the LOR gene. This alteration results from a T to C substitution at nucleotide position 46, causing the cysteine (C) at amino acid position 16 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

0.79

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.27

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PROVEAN

Pathogenic

-10

REVEL

Benign

0.13

Sift4G

Benign

0.19

Polyphen

0.96

Vest4

0.57

MVP

0.57

ClinPred

0.22

GERP RS

1.8

Varity_R

0.55

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over