rs587281

Variant names:

• chr1-183243185-C-T
• rs587281
• NM_005562.3:c.3367C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-183243185-C-T
• chr1-183243185-C-A
• chr1-183243185-C-G

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.3367C>T​(p.Leu1123Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,582,926 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (324 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (295 hom.)
• Consequence: LAMC2 NM_005562.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.89
• Publications: 1 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
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• 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=-0.77).
• BP6: Variant 1-183243185-C-T is Benign according to our data. Variant chr1-183243185-C-T is described in ClinVar as Benign. ClinVar VariationId is 259788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	NM_005562.3	MANE Select	c.3367C>T	p.Leu1123Leu	synonymous	Exon 23 of 23	NP_005553.2	Q13753-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	ENST00000264144.5	TSL:1 MANE Select	c.3367C>T	p.Leu1123Leu	synonymous	Exon 23 of 23	ENSP00000264144.4	Q13753-1
	LAMC2	ENST00000914499.1		c.3391C>T	p.Leu1131Leu	synonymous	Exon 23 of 23	ENSP00000584558.1
	LAMC2	ENST00000878927.1		c.3244C>T	p.Leu1082Leu	synonymous	Exon 22 of 22	ENSP00000548986.1

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 5497 AN: 133102 Hom.: 321 Cov.: 31

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000714

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0261

Gnomad NFE AF: 0.000777

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.00923 AC: 2317 AN: 251056 AF XY: 0.00672

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00554

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00412 AC: 5975 AN: 1449708 Hom.: 295 Cov.: 31 AF XY: 0.00362 AC XY: 2609 AN XY: 720912

African (AFR) AF: 0.134 AC: 4442 AN: 33130

American (AMR) AF: 0.00661 AC: 285 AN: 43142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 38678

South Asian (SAS) AF: 0.000345 AC: 29 AN: 84166

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53174

Middle Eastern (MID) AF: 0.00714 AC: 41 AN: 5740

European-Non Finnish (NFE) AF: 0.000572 AC: 633 AN: 1105976

Other (OTH) AF: 0.00908 AC: 543 AN: 59808

GnomAD4 genome AF: 0.0413 AC: 5508 AN: 133218 Hom.: 324 Cov.: 31 AF XY: 0.0400 AC XY: 2626 AN XY: 65730

African (AFR) AF: 0.142 AC: 5173 AN: 36370

American (AMR) AF: 0.0173 AC: 235 AN: 13594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3046

East Asian (EAS) AF: 0.00 AC: 0 AN: 4282

South Asian (SAS) AF: 0.000714 AC: 3 AN: 4200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9784

Middle Eastern (MID) AF: 0.0288 AC: 6 AN: 208

European-Non Finnish (NFE) AF: 0.000761 AC: 45 AN: 59168

Other (OTH) AF: 0.0256 AC: 46 AN: 1800

Alfa AF: 0.0167 Hom.: 96

Bravo AF: 0.0411

EpiCase AF: 0.00136

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Junctional epidermolysis bullosa (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.059
DANN	Benign	0.55
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs587281; hg19: chr1-183212320;