rs2274980

Variant names:

• chr1-183215481-C-T
• rs2274980
• NM_005562.3:c.297C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-183215481-C-T
• chr1-183215481-C-A
• chr1-183215481-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005562.3(LAMC2):​c.297C>T​(p.Ser99Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,613,682 control chromosomes in the GnomAD database, including 41,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5778 hom., cov: 32)
  • Exomes 𝑓: 0.21 (35749 hom.)
• Consequence: LAMC2 NM_005562.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.425
• Publications: 20 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
• junctional epidermolysis bullosa, non-Herlitz type

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-183215481-C-T is Benign according to our data. Variant chr1-183215481-C-T is described in ClinVar as Benign. ClinVar VariationId is 259787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.425 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	NM_005562.3	MANE Select	c.297C>T	p.Ser99Ser	synonymous	Exon 3 of 23	NP_005553.2	Q13753-1
	LAMC2	NM_018891.3		c.297C>T	p.Ser99Ser	synonymous	Exon 3 of 22	NP_061486.2	Q13753-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	ENST00000264144.5	TSL:1 MANE Select	c.297C>T	p.Ser99Ser	synonymous	Exon 3 of 23	ENSP00000264144.4	Q13753-1
	LAMC2	ENST00000493293.5	TSL:1	c.297C>T	p.Ser99Ser	synonymous	Exon 3 of 22	ENSP00000432063.1	Q13753-2
	LAMC2	ENST00000914499.1		c.297C>T	p.Ser99Ser	synonymous	Exon 3 of 23	ENSP00000584558.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38907 AN: 151844 Hom.: 5744 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.248 AC: 62331 AN: 251404 AF XY: 0.241

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.343

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.209 AC: 306023 AN: 1461720 Hom.: 35749 Cov.: 34 AF XY: 0.211 AC XY: 153397 AN XY: 727172

African (AFR) AF: 0.395 AC: 13227 AN: 33470

American (AMR) AF: 0.370 AC: 16563 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4355 AN: 26136

East Asian (EAS) AF: 0.395 AC: 15688 AN: 39698

South Asian (SAS) AF: 0.311 AC: 26848 AN: 86254

European-Finnish (FIN) AF: 0.184 AC: 9835 AN: 53418

Middle Eastern (MID) AF: 0.130 AC: 747 AN: 5754

European-Non Finnish (NFE) AF: 0.185 AC: 205338 AN: 1111882

Other (OTH) AF: 0.222 AC: 13422 AN: 60384

GnomAD4 genome AF: 0.257 AC: 39003 AN: 151962 Hom.: 5778 Cov.: 32 AF XY: 0.258 AC XY: 19176 AN XY: 74292

African (AFR) AF: 0.388 AC: 16035 AN: 41368

American (AMR) AF: 0.290 AC: 4427 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3470

East Asian (EAS) AF: 0.351 AC: 1809 AN: 5160

South Asian (SAS) AF: 0.310 AC: 1495 AN: 4816

European-Finnish (FIN) AF: 0.189 AC: 2003 AN: 10580

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12066 AN: 67972

Other (OTH) AF: 0.216 AC: 456 AN: 2110

Alfa AF: 0.210 Hom.: 12010

Bravo AF: 0.271

Asia WGS AF: 0.335 AC: 1164 AN: 3478

EpiCase AF: 0.170

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Junctional epidermolysis bullosa (1)
-	-	1	Junctional epidermolysis bullosa gravis of Herlitz (1)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		-0.42
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2274980; hg19: chr1-183184616; COSMIC: COSV51453066;