Genetic Variant NM_178351.4:c.317G>A (chr1-152805162-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_178351.4(LCE1C):c.317G>A(p.Cys106Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,612,220 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 22 hom., cov: 31)

Exomes 𝑓: 0.00070 ( 9 hom. )

Consequence

LCE1C
NM_178351.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.47

Publications

3 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005890101).

BP6

Variant 1-152805162-C-T is Benign according to our data. Variant chr1-152805162-C-T is described in ClinVar as [Benign]. Clinvar id is 787217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00709 (1079/152280) while in subpopulation AFR AF = 0.0248 (1032/41568). AF 95% confidence interval is 0.0236. There are 22 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCE1C	NM_178351.4 link	c.317G>A	p.Cys106Tyr	missense_variant	Exon 2 of 2	ENST00000607093.2	NP_848128.1	Q5T751
LCE1C	NM_001276331.2 link	c.227G>A	p.Cys76Tyr	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.317G>A	p.Cys106Tyr	missense_variant	Exon 2 of 2	6	NM_178351.4	ENSP00000475270.1		Q5T751
LCE1C	ENST00000606576.1 link	c.*64G>A		downstream_gene_variant		3		ENSP00000476034.1		U3KQM4

Frequencies

GnomAD3 genomes

AF:

0.00708

AC:

1078

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

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:

0.00

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00173

AC:

430

AN:

247872

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.0246

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000701

AC:

1024

AN:

1459940

Hom.:

Cov.:

AF XY:

0.000609

AC XY:

442

AN XY:

726118

show subpopulations

African (AFR)

AF:

0.0246

AC:

823

AN:

33418

American (AMR)

AF:

0.00128

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000198

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.000541

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111048

Other (OTH)

AF:

0.00199

AC:

120

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00709

AC:

1079

AN:

152280

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

479

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0248

AC:

1032

AN:

41568

American (AMR)

AF:

0.00235

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00190

Hom.:

Bravo

AF:

0.00809

ESP6500AA

AF:

0.0224

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00220

AC:

267

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.044

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

3.5

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.55

MVP

0.22

ClinPred

0.042

GERP RS

2.9

Varity_R

0.73

gMVP

0.040

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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NM_178351.4:c.317G>A

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