NM_178434.3:c.196C>T

Variant names:

• chr1-152600927-C-T
• rs768103728
• NM_178434.3:c.196C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_178434.3(LCE3C):​c.196C>T​(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 949,384 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000031 (1 hom., cov: 16)
  • Exomes 𝑓: 0.000022 (6 hom.)
• Consequence: LCE3C NM_178434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.07
• Publications: 1 publications found

Genes affected

LCE3C (HGNC:16612): (late cornified envelope 3C) Involved in defense response to Gram-negative bacterium; defense response to Gram-positive bacterium; and killing of cells of other organism. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14010462).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178434.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCE3C	NM_178434.3	MANE Select	c.196C>T	p.Arg66Trp	missense	Exon 2 of 2	NP_848521.1	Q5T5A8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCE3C	ENST00000684028.1	MANE Select	c.196C>T	p.Arg66Trp	missense	Exon 2 of 2	ENSP00000507204.1	Q5T5A8
	LCE3C	ENST00000333881.3	TSL:6	c.196C>T	p.Arg66Trp	missense	Exon 1 of 1	ENSP00000334644.3	Q5T5A8

Frequencies

GnomAD3 genomes AF: 0.0000315 AC: 3 AN: 95364 Hom.: 1 Cov.: 16

Gnomad AFR AF: 0.0000619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000388

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000198 AC: 3 AN: 151384 AF XY: 0.0000369

Gnomad AFR exome AF: 0.000225

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 19 AN: 854020 Hom.: 6 Cov.: 27 AF XY: 0.0000306 AC XY: 13 AN XY: 424492

African (AFR) AF: 0.000145 AC: 4 AN: 27576

American (AMR) AF: 0.00 AC: 0 AN: 26850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15856

East Asian (EAS) AF: 0.00 AC: 0 AN: 25248

South Asian (SAS) AF: 0.0000196 AC: 1 AN: 50944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3662

European-Non Finnish (NFE) AF: 0.0000204 AC: 13 AN: 637160

Other (OTH) AF: 0.0000275 AC: 1 AN: 36396

GnomAD4 genome AF: 0.0000315 AC: 3 AN: 95364 Hom.: 1 Cov.: 16 AF XY: 0.0000218 AC XY: 1 AN XY: 45888

African (AFR) AF: 0.0000619 AC: 2 AN: 32286

American (AMR) AF: 0.00 AC: 0 AN: 8810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2106

East Asian (EAS) AF: 0.00 AC: 0 AN: 2994

South Asian (SAS) AF: 0.000388 AC: 1 AN: 2576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 38918

Other (OTH) AF: 0.00 AC: 0 AN: 1318

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.74
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.94	T
PhyloP100		-2.1
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Benign	0.076
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.10	T
Polyphen		0.98	D
Vest4		0.28
MutPred		0.22		Gain of catalytic residue at R66 (P = 0.0182)
MVP		0.32
MPC		0.78
ClinPred		0.22	T
GERP RS		-0.028
PromoterAI		-0.014	Neutral
Varity_R		0.24
gMVP		0.058
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs768103728; hg19: chr1-152573403; COSMIC: COSV107378248;