chr1-183232835-G-C

Position:

chr1-183232835-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005562.3(LAMC2):c.2198G>C(p.Ser733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,736 control chromosomes in the GnomAD database, including 17,375 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S733S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.16 ( 2149 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15226 hom. )

Consequence

LAMC2
NM_005562.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.30

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030424297).

BP6

Variant 1-183232835-G-C is Benign according to our data. Variant chr1-183232835-G-C is described in ClinVar as [Benign]. Clinvar id is 259784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183232835-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 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.2198G>C	p.Ser733Thr	missense_variant	14/23	ENST00000264144.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC2	ENST00000264144.5 linkuse as main transcript	c.2198G>C	p.Ser733Thr	missense_variant	14/23	1	NM_005562.3	P1	Q13753-1
LAMC2	ENST00000493293.5 linkuse as main transcript	c.2198G>C	p.Ser733Thr	missense_variant	14/22	1			Q13753-2

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24451

AN:

152006

Hom.:

2136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.0856

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.116

GnomAD3 exomes

AF:

0.140

AC:

35293

AN:

251286

Hom.:

2780

AF XY:

0.135

AC XY:

18308

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.229

Gnomad AMR exome

AF:

0.170

Gnomad ASJ exome

AF:

0.0979

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.0914

Gnomad FIN exome

AF:

0.155

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.140

AC:

204435

AN:

1461612

Hom.:

15226

Cov.:

AF XY:

0.138

AC XY:

100236

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.232

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.100

Gnomad4 EAS exome

AF:

0.224

Gnomad4 SAS exome

AF:

0.0927

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.142

GnomAD4 genome

AF:

0.161

AC:

24502

AN:

152124

Hom.:

2149

Cov.:

AF XY:

0.161

AC XY:

11965

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.190

Gnomad4 SAS

AF:

0.0855

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.135

Hom.:

477

Bravo

AF:

0.165

TwinsUK

AF:

0.138

AC:

510

ALSPAC

AF:

0.141

AC:

543

ESP6500AA

AF:

0.226

AC:

997

ESP6500EA

AF:

0.129

AC:

1107

ExAC

AF:

0.138

AC:

16767

Asia WGS

AF:

0.122

AC:

424

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.079

.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

0.94

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.066

Sift

Benign

0.051

T;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.17

B;B

Vest4

0.21

MPC

0.18

ClinPred

0.014

GERP RS

1.7

Varity_R

0.066

gMVP

0.36

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

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