1-183186347-C-A

Position:

• chr1-183186347-C-A

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.-6C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,592,980 control chromosomes in the GnomAD database, including 71,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5797 hom., cov: 33)
  • Exomes 𝑓: 0.30 (65915 hom.)
• Consequence: LAMC2 NM_005562.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.433

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=-0.53).
• BP6: Variant 1-183186347-C-A is Benign according to our data. Variant chr1-183186347-C-A is described in ClinVar as [Benign]. Clinvar id is 293983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC2	NM_005562.3	c.-6C>A		5_prime_UTR_variant	1/23	ENST00000264144.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC2	ENST00000264144.5	c.-6C>A		5_prime_UTR_variant	1/23	1	NM_005562.3	P1
LAMC2	ENST00000493293.5	c.-6C>A		5_prime_UTR_variant	1/22	1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38975 AN: 151946 Hom.: 5789 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.312 AC: 67186 AN: 215182 Hom.: 10839 AF XY: 0.316 AC XY: 37592 AN XY: 119080

Gnomad AFR exome AF: 0.0999

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.419

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.298 AC: 429504 AN: 1440918 Hom.: 65915 Cov.: 38 AF XY: 0.300 AC XY: 215003 AN XY: 716306

Gnomad4 AFR exome AF: 0.0915

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.358

Gnomad4 FIN exome AF: 0.398

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.256 AC: 38993 AN: 152062 Hom.: 5797 Cov.: 33 AF XY: 0.266 AC XY: 19736 AN XY: 74298

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.279

Alfa AF: 0.269 Hom.: 1437

Bravo AF: 0.238

Asia WGS AF: 0.378 AC: 1313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 13, 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
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs684527; hg19: chr1-183155482;