1-183218468-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005562.3(LAMC2):c.483C>T(p.Val161Val) 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:7

Conservation

PhyloP100: 0.746

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

junctional epidermolysis bullosa
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
junctional epidermolysis bullosa Herlitz type
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, PanelApp Australia
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LAMC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 259789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
LAMC2	NM_005562.3 link	c.483C>T	p.Val161Val	synonymous_variant	Exon 4 of 23	ENST00000264144.5	NP_005553.2	Q13753-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC2	ENST00000264144.5 link	c.483C>T	p.Val161Val	synonymous_variant	Exon 4 of 23	1	NM_005562.3	ENSP00000264144.4		Q13753-1
LAMC2	ENST00000493293.5 link	c.483C>T	p.Val161Val	synonymous_variant	Exon 4 of 22	1		ENSP00000432063.1		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

GnomAD2 exomes

AF:

0.248

AC:

61548

AN:

247984

AF XY:

0.241

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 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

African (AFR)

AF:

0.395

AC:

13224

AN:

33446

American (AMR)

AF:

0.371

AC:

16556

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

4352

AN:

26126

East Asian (EAS)

AF:

0.395

AC:

15682

AN:

39676

South Asian (SAS)

AF:

0.311

AC:

26823

AN:

86166

European-Finnish (FIN)

AF:

0.184

AC:

9824

AN:

53352

Middle Eastern (MID)

AF:

0.130

AC:

748

AN:

5766

European-Non Finnish (NFE)

AF:

0.185

AC:

205018

AN:

1111002

Other (OTH)

AF:

0.222

AC:

13402

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11966

23932

35899

47865

59831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7660

15320

22980

30640

38300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.257

AC:

39055

AN:

152112

Hom.:

5790

Cov.:

AF XY:

0.258

AC XY:

19195

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.388

AC:

16069

AN:

41454

American (AMR)

AF:

0.290

AC:

4427

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

595

AN:

3472

East Asian (EAS)

AF:

0.349

AC:

1804

AN:

5162

South Asian (SAS)

AF:

0.311

AC:

1502

AN:

4828

European-Finnish (FIN)

AF:

0.189

AC:

2002

AN:

10586

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12081

AN:

68012

Other (OTH)

AF:

0.216

AC:

456

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1455

2909

4364

5818

7273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.212

Hom.:

2991

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 27, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15370542) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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 13, 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

-0.29

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.75

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over