rs1047981

Variant names:

• chr1-183237438-G-A
• rs1047981
• NM_005562.3:c.2688G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005562.3(LAMC2):​c.2688G>A​(p.Gln896Gln) 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 1,613,376 control chromosomes in the GnomAD database, including 46,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8133 hom., cov: 32)
  • Exomes 𝑓: 0.21 (37989 hom.)
• Consequence: LAMC2 NM_005562.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.360
• Publications: 17 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-183237438-G-A is Benign according to our data. Variant chr1-183237438-G-A is described in ClinVar as Benign. ClinVar VariationId is 259786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	NM_005562.3	MANE Select	c.2688G>A	p.Gln896Gln	synonymous	Exon 18 of 23	NP_005553.2
	LAMC2	NM_018891.3		c.2688G>A	p.Gln896Gln	synonymous	Exon 18 of 22	NP_061486.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	ENST00000264144.5	TSL:1 MANE Select	c.2688G>A	p.Gln896Gln	synonymous	Exon 18 of 23	ENSP00000264144.4
	LAMC2	ENST00000493293.5	TSL:1	c.2688G>A	p.Gln896Gln	synonymous	Exon 18 of 22	ENSP00000432063.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44418 AN: 152002 Hom.: 8099 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.258 AC: 64719 AN: 251246 AF XY: 0.248

Gnomad AFR exome AF: 0.511

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.343

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.213 AC: 311566 AN: 1461256 Hom.: 37989 Cov.: 33 AF XY: 0.214 AC XY: 155811 AN XY: 726986

African (AFR) AF: 0.516 AC: 17256 AN: 33466

American (AMR) AF: 0.378 AC: 16916 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4349 AN: 26134

East Asian (EAS) AF: 0.394 AC: 15650 AN: 39692

South Asian (SAS) AF: 0.312 AC: 26899 AN: 86248

European-Finnish (FIN) AF: 0.185 AC: 9856 AN: 53416

Middle Eastern (MID) AF: 0.140 AC: 810 AN: 5766

European-Non Finnish (NFE) AF: 0.185 AC: 205913 AN: 1111448

Other (OTH) AF: 0.231 AC: 13917 AN: 60372

GnomAD4 genome AF: 0.293 AC: 44518 AN: 152120 Hom.: 8133 Cov.: 32 AF XY: 0.293 AC XY: 21783 AN XY: 74358

African (AFR) AF: 0.509 AC: 21098 AN: 41458

American (AMR) AF: 0.307 AC: 4690 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3470

East Asian (EAS) AF: 0.352 AC: 1819 AN: 5174

South Asian (SAS) AF: 0.312 AC: 1506 AN: 4822

European-Finnish (FIN) AF: 0.190 AC: 2011 AN: 10586

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12157 AN: 67996

Other (OTH) AF: 0.243 AC: 514 AN: 2114

Alfa AF: 0.236 Hom.: 4338

Bravo AF: 0.311

Asia WGS AF: 0.341 AC: 1184 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.169

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Junctional epidermolysis bullosa (1)
-	-	1	Junctional epidermolysis bullosa gravis of Herlitz (1)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.20
DANN	Benign	0.52
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1047981; hg19: chr1-183206573; COSMIC: COSV51453550; COSMIC: COSV51453550;