rs2276542

Variant names:

• chr1-183186264-A-G
• rs2276542
• ENST00000264144:c.-89A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-183186264-A-G
• chr1-183186264-A-T

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.-89A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,523,410 control chromosomes in the GnomAD database, including 27,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2653 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24439 hom.)
• Consequence: LAMC2 NM_005562.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.72

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 (BayesDel_noAF=-0.66).
• BP6: Variant 1-183186264-A-G is Benign according to our data. Variant chr1-183186264-A-G is described in ClinVar as [Benign]. Clinvar id is 293979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMC2	NM_005562.3	c.-89A>G		5_prime_UTR_variant	Exon 1 of 23	ENST00000264144.5	NP_005553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC2	ENST00000264144	c.-89A>G		5_prime_UTR_variant	Exon 1 of 23	1	NM_005562.3	ENSP00000264144.4
LAMC2	ENST00000493293	c.-89A>G		5_prime_UTR_variant	Exon 1 of 22	1		ENSP00000432063.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27546 AN: 152080 Hom.: 2655 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.181 AC: 248536 AN: 1371212 Hom.: 24439 Cov.: 35 AF XY: 0.181 AC XY: 121954 AN XY: 674750

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.181 AC: 27559 AN: 152198 Hom.: 2653 Cov.: 33 AF XY: 0.181 AC XY: 13454 AN XY: 74416

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.164

Alfa AF: 0.180 Hom.: 473

Bravo AF: 0.193

Asia WGS AF: 0.247 AC: 856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2276542; hg19: chr1-183155399; COSMIC: COSV51459231; COSMIC: COSV51459231;