1-183186354-T-C

Position:

• chr1-183186354-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_005562.3(LAMC2):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LAMC2 NM_005562.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.71

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_005562.3 (LAMC2) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 293984
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-183186354-T-C is Pathogenic according to our data. Variant chr1-183186354-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 488888.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC2	NM_005562.3	c.2T>C	p.Met1?	start_lost	1/23	ENST00000264144.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC2	ENST00000264144.5	c.2T>C	p.Met1?	start_lost	1/23	1	NM_005562.3	P1
LAMC2	ENST00000493293.5	c.2T>C	p.Met1?	start_lost	1/22	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448066 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2016

The c.2 T>C pathogenic variant in the LAMC2 gene has not been reported previously and is found at the conserved Methionine initiation codon of LAMC2 on both alleles, consistent with reported consanguinity in the parents of this child. It was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2 T>C pathogenic variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. We interpret p.Met1? as a pathogenic variant." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.61
MutPred		0.79		Gain of catalytic residue at M1 (P = 0.0392);Gain of catalytic residue at M1 (P = 0.0392);
MVP		0.67
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.67

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: rs1553262199; hg19: chr1-183155489;