1-183208083-A-G

Position:

• chr1-183208083-A-G

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.268+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,609,348 control chromosomes in the GnomAD database, including 160,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16149 hom., cov: 31)
  • Exomes 𝑓: 0.44 (144024 hom.)
• Consequence: LAMC2 NM_005562.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.37

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=-0.97).
• BP6: Variant 1-183208083-A-G is Benign according to our data. Variant chr1-183208083-A-G is described in ClinVar as [Benign]. Clinvar id is 259785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC2	NM_005562.3	c.268+14A>G		intron_variant		ENST00000264144.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC2	ENST00000264144.5	c.268+14A>G		intron_variant		1	NM_005562.3	P1
LAMC2	ENST00000493293.5	c.268+14A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69541 AN: 151674 Hom.: 16114 Cov.: 31

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.481

GnomAD3 exomes AF: 0.473 AC: 118818 AN: 251088 Hom.: 28412 AF XY: 0.472 AC XY: 64009 AN XY: 135718

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.563

Gnomad SAS exome AF: 0.516

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.442 AC: 644113 AN: 1457556 Hom.: 144024 Cov.: 33 AF XY: 0.443 AC XY: 321670 AN XY: 725316

Gnomad4 AFR exome AF: 0.465

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.512

Gnomad4 FIN exome AF: 0.495

Gnomad4 NFE exome AF: 0.428

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.459 AC: 69626 AN: 151792 Hom.: 16149 Cov.: 31 AF XY: 0.465 AC XY: 34470 AN XY: 74154

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.480

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.510

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.429

Gnomad4 OTH AF: 0.486

Alfa AF: 0.435 Hom.: 15491

Bravo AF: 0.457

Asia WGS AF: 0.553 AC: 1922 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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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 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	-0.97
CADD	Benign	0.067
DANN	Benign	0.50

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: rs647347; hg19: chr1-183177218; COSMIC: COSV51456075;