1-183218468-C-T

Position:

chr1-183218468-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005562.3(LAMC2):c.483C>T(p.Val161=) 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 1,612,612 control chromosomes in the GnomAD database, including 41,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5790 hom., cov: 32)

Exomes 𝑓: 0.21 ( 35719 hom. )

Consequence

LAMC2
NM_005562.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.746

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 1-183218468-C-T is Benign according to our data. Variant chr1-183218468-C-T is described in ClinVar as [Benign]. Clinvar id is 259789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183218468-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.746 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC2	NM_005562.3 linkuse as main transcript	c.483C>T	p.Val161=	synonymous_variant	4/23	ENST00000264144.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC2	ENST00000264144.5 linkuse as main transcript	c.483C>T	p.Val161=	synonymous_variant	4/23	1	NM_005562.3	P1	Q13753-1
LAMC2	ENST00000493293.5 linkuse as main transcript	c.483C>T	p.Val161=	synonymous_variant	4/22	1			Q13753-2

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38959

AN:

151994

Hom.:

5756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.387

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.289

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.349

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.215

GnomAD3 exomes

AF:

0.248

AC:

61548

AN:

247984

Hom.:

8812

AF XY:

0.241

AC XY:

32335

AN XY:

134148

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.166

Gnomad EAS exome

AF:

0.342

Gnomad SAS exome

AF:

0.315

Gnomad FIN exome

AF:

0.181

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.209

AC:

305629

AN:

1460500

Hom.:

35719

Cov.:

AF XY:

0.211

AC XY:

153190

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.395

Gnomad4 AMR exome

AF:

0.371

Gnomad4 ASJ exome

AF:

0.167

Gnomad4 EAS exome

AF:

0.395

Gnomad4 SAS exome

AF:

0.311

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.185

Gnomad4 OTH exome

AF:

0.222

GnomAD4 genome

AF:

0.257

AC:

39055

AN:

152112

Hom.:

5790

Cov.:

AF XY:

0.258

AC XY:

19195

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.388

Gnomad4 AMR

AF:

0.290

Gnomad4 ASJ

AF:

0.171

Gnomad4 EAS

AF:

0.349

Gnomad4 SAS

AF:

0.311

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.178

Gnomad4 OTH

AF:

0.216

Alfa

AF:

0.211

Hom.:

2622

Bravo

AF:

0.271

Asia WGS

AF:

0.335

AC:

1164

AN:

3478

EpiCase

AF:

0.170

EpiControl

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	This variant is associated with the following publications: (PMID: 15370542) -

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

-0.29

CADD

Benign

DANN

Benign

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over