1-183208083-A-G

Variant names:

• chr1-183208083-A-G
• rs647347
• NM_005562.3:c.268+14A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005562.3(LAMC2):​c.268+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,609,348 control chromosomes in the GnomAD database, including 160,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16149 hom., cov: 31)
  • Exomes 𝑓: 0.44 (144024 hom.)
• Consequence: LAMC2 NM_005562.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 1-183208083-A-G is Benign according to our data. Variant chr1-183208083-A-G is described in ClinVar as Benign. ClinVar VariationId is 259785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.535 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.268+14A>G		intron	N/A	NP_005553.2	Q13753-1
	LAMC2	NM_018891.3		c.268+14A>G		intron	N/A	NP_061486.2	Q13753-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC2	ENST00000264144.5	TSL:1 MANE Select	c.268+14A>G		intron	N/A	ENSP00000264144.4	Q13753-1
	LAMC2	ENST00000493293.5	TSL:1	c.268+14A>G		intron	N/A	ENSP00000432063.1	Q13753-2
	LAMC2	ENST00000914499.1		c.268+14A>G		intron	N/A	ENSP00000584558.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69541 AN: 151674 Hom.: 16114 Cov.: 31

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.481

GnomAD2 exomes AF: 0.473 AC: 118818 AN: 251088 AF XY: 0.472

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.563

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.442 AC: 644113 AN: 1457556 Hom.: 144024 Cov.: 33 AF XY: 0.443 AC XY: 321670 AN XY: 725316

African (AFR) AF: 0.465 AC: 15531 AN: 33386

American (AMR) AF: 0.502 AC: 22462 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 10459 AN: 26110

East Asian (EAS) AF: 0.533 AC: 21133 AN: 39680

South Asian (SAS) AF: 0.512 AC: 44088 AN: 86170

European-Finnish (FIN) AF: 0.495 AC: 26436 AN: 53376

Middle Eastern (MID) AF: 0.498 AC: 2852 AN: 5728

European-Non Finnish (NFE) AF: 0.428 AC: 474404 AN: 1108182

Other (OTH) AF: 0.444 AC: 26748 AN: 60210

GnomAD4 genome AF: 0.459 AC: 69626 AN: 151792 Hom.: 16149 Cov.: 31 AF XY: 0.465 AC XY: 34470 AN XY: 74154

African (AFR) AF: 0.468 AC: 19338 AN: 41340

American (AMR) AF: 0.480 AC: 7317 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1408 AN: 3470

East Asian (EAS) AF: 0.552 AC: 2845 AN: 5154

South Asian (SAS) AF: 0.510 AC: 2449 AN: 4806

European-Finnish (FIN) AF: 0.520 AC: 5472 AN: 10522

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29131 AN: 67948

Other (OTH) AF: 0.486 AC: 1022 AN: 2104

Alfa AF: 0.437 Hom.: 20167

Bravo AF: 0.457

Asia WGS AF: 0.553 AC: 1922 AN: 3478

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	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	-0.97
CADD	Benign	0.067
DANN	Benign	0.50
PhyloP100		-1.4
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: rs647347; hg19: chr1-183177218; COSMIC: COSV51456075;