1-183232835-G-C

Variant names:

• chr1-183232835-G-C
• rs2296303
• NM_005562.3:c.2198G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:7
• Conservation: PhyloP100: 1.30
• Publications: 16 publications found

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]

LAMC2 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• junctional epidermolysis bullosa Herlitz type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, PanelApp Australia
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	NM_005562.3	MANE Select	c.2198G>C	p.Ser733Thr	missense	Exon 14 of 23	NP_005553.2
	LAMC2	NM_018891.3		c.2198G>C	p.Ser733Thr	missense	Exon 14 of 22	NP_061486.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	ENST00000264144.5	TSL:1 MANE Select	c.2198G>C	p.Ser733Thr	missense	Exon 14 of 23	ENSP00000264144.4
	LAMC2	ENST00000493293.5	TSL:1	c.2198G>C	p.Ser733Thr	missense	Exon 14 of 22	ENSP00000432063.1

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

GnomAD2 exomes AF: 0.140 AC: 35293 AN: 251286 AF XY: 0.135

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 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

African (AFR) AF: 0.232 AC: 7779 AN: 33468

American (AMR) AF: 0.171 AC: 7647 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2623 AN: 26132

East Asian (EAS) AF: 0.224 AC: 8889 AN: 39698

South Asian (SAS) AF: 0.0927 AC: 7996 AN: 86246

European-Finnish (FIN) AF: 0.158 AC: 8414 AN: 53414

Middle Eastern (MID) AF: 0.0470 AC: 271 AN: 5766

European-Non Finnish (NFE) AF: 0.137 AC: 152219 AN: 1111792

Other (OTH) AF: 0.142 AC: 8597 AN: 60378

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

African (AFR) AF: 0.232 AC: 9615 AN: 41462

American (AMR) AF: 0.153 AC: 2342 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3472

East Asian (EAS) AF: 0.190 AC: 980 AN: 5166

South Asian (SAS) AF: 0.0855 AC: 413 AN: 4830

European-Finnish (FIN) AF: 0.157 AC: 1662 AN: 10594

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8810 AN: 68000

Other (OTH) AF: 0.115 AC: 243 AN: 2110

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

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

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Junctional epidermolysis bullosa Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.066
Sift	Benign	0.051	T
Sift4G	Uncertain	0.021	D
Polyphen		0.17	B
Vest4		0.21
MPC		0.18
ClinPred		0.014	T
GERP RS		1.7
Varity_R		0.066
gMVP		0.36
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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