rs1047980

Positions:

• chr1-183223169-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005562.3(LAMC2):​c.798T>G​(p.Gly266=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,613,538 control chromosomes in the GnomAD database, including 46,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8197 hom., cov: 32)
  • Exomes 𝑓: 0.21 (38147 hom.)
• Consequence: LAMC2 NM_005562.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.390

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-183223169-T-G is Benign according to our data. Variant chr1-183223169-T-G is described in ClinVar as [Benign]. Clinvar id is 259790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183223169-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMC2	NM_005562.3	c.798T>G	p.Gly266=	synonymous_variant	7/23	ENST00000264144.5	NP_005553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC2	ENST00000264144.5	c.798T>G	p.Gly266=	synonymous_variant	7/23	1	NM_005562.3	ENSP00000264144	P1
LAMC2	ENST00000493293.5	c.798T>G	p.Gly266=	synonymous_variant	7/22	1		ENSP00000432063

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44536 AN: 151948 Hom.: 8160 Cov.: 32

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.244

GnomAD3 exomes AF: 0.258 AC: 64833 AN: 251070 Hom.: 10032 AF XY: 0.248 AC XY: 33714 AN XY: 135736

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.344

Gnomad SAS exome AF: 0.317

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.214 AC: 312080 AN: 1461472 Hom.: 38147 Cov.: 34 AF XY: 0.215 AC XY: 156044 AN XY: 727036

Gnomad4 AFR exome AF: 0.520

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.294 AC: 44640 AN: 152066 Hom.: 8197 Cov.: 32 AF XY: 0.294 AC XY: 21841 AN XY: 74332

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.244

Alfa AF: 0.197 Hom.: 6503

Bravo AF: 0.312

Asia WGS AF: 0.343 AC: 1191 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.169

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	This variant is associated with the following publications: (PMID: 15370542) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 12, 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	-0.52
CADD	Benign	8.6
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs1047980; hg19: chr1-183192304; COSMIC: COSV51453536;