1-183232835-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005562.3(LAMC2):c.2198G>C(p.Ser733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,736 control chromosomes in the GnomAD database, including 17,375 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S733S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2149 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15226 hom.)
• Consequence: LAMC2 NM_005562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.30

Genes affected

LAMC2 (HGNC:6493): (laminin subunit gamma 2) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), have a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 2. The gamma 2 chain, formerly thought to be a truncated version of beta chain (B2t), is highly homologous to the gamma 1 chain; however, it lacks domain VI, and domains V, IV and III are shorter. It is expressed in several fetal tissues but differently from gamma 1, and is specifically localized to epithelial cells in skin, lung and kidney. The gamma 2 chain together with alpha 3 and beta 3 chains constitute laminin 5 (earlier known as kalinin), which is an integral part of the anchoring filaments that connect epithelial cells to the underlying basement membrane. The epithelium-specific expression of the gamma 2 chain implied its role as an epithelium attachment molecule, and mutations in this gene have been associated with junctional epidermolysis bullosa, a skin disease characterized by blisters due to disruption of the epidermal-dermal junction. Two transcript variants resulting from alternative splicing of the 3' terminal exon, and encoding different isoforms of gamma 2 chain, have been described. The two variants are differentially expressed in embryonic tissues, however, the biological significance of the two forms is not known. Transcript variants utilizing alternative polyA_signal have also been noted in literature. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030424297).
• BP6: Variant 1-183232835-G-C is Benign according to our data. Variant chr1-183232835-G-C is described in ClinVar as [Benign]. Clinvar id is 259784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183232835-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC2	NM_005562.3	c.2198G>C	p.Ser733Thr	missense_variant	14/23	ENST00000264144.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC2	ENST00000264144.5	c.2198G>C	p.Ser733Thr	missense_variant	14/23	1	NM_005562.3	P1
LAMC2	ENST00000493293.5	c.2198G>C	p.Ser733Thr	missense_variant	14/22	1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24451 AN: 152006 Hom.: 2136 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0856

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.140 AC: 35293 AN: 251286 Hom.: 2780 AF XY: 0.135 AC XY: 18308 AN XY: 135832

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.0979

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.0914

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.140 AC: 204435 AN: 1461612 Hom.: 15226 Cov.: 34 AF XY: 0.138 AC XY: 100236 AN XY: 727118

Gnomad4 AFR exome AF: 0.232

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.0927

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.161 AC: 24502 AN: 152124 Hom.: 2149 Cov.: 32 AF XY: 0.161 AC XY: 11965 AN XY: 74370

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.0855

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.115

Alfa AF: 0.135 Hom.: 477

Bravo AF: 0.165

TwinsUK AF: 0.138 AC: 510

ALSPAC AF: 0.141 AC: 543

ESP6500AA AF: 0.226 AC: 997

ESP6500EA AF: 0.129 AC: 1107

ExAC AF: 0.138 AC: 16767

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	14
Dann	Benign	0.91
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.94	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.066
Sift	Benign	0.051	T;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.17	B;B
Vest4		0.21
MPC		0.18
ClinPred		0.014	T
GERP RS		1.7
Varity_R		0.066
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs2296303; hg19: chr1-183201970; COSMIC: COSV51456358;