NM_005562.3:c.-89A>G

Variant names:

• chr1-183186264-A-G
• rs2276542
• NM_005562.3:c.-89A>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.-89A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,523,410 control chromosomes in the GnomAD database, including 27,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2653 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24439 hom.)
• Consequence: LAMC2 NM_005562.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.72
• 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=-0.66).
• BP6: Variant 1-183186264-A-G is Benign according to our data. Variant chr1-183186264-A-G is described in ClinVar as Benign. ClinVar VariationId is 293979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 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.-89A>G		5_prime_UTR	Exon 1 of 23	NP_005553.2	Q13753-1
	LAMC2	NM_018891.3		c.-89A>G		5_prime_UTR	Exon 1 of 22	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.-89A>G		5_prime_UTR	Exon 1 of 23	ENSP00000264144.4	Q13753-1
	LAMC2	ENST00000493293.5	TSL:1	c.-89A>G		5_prime_UTR	Exon 1 of 22	ENSP00000432063.1	Q13753-2
	LAMC2	ENST00000878927.1		c.-89A>G		5_prime_UTR	Exon 1 of 22	ENSP00000548986.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27546 AN: 152080 Hom.: 2655 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.181 AC: 248536 AN: 1371212 Hom.: 24439 Cov.: 35 AF XY: 0.181 AC XY: 121954 AN XY: 674750

African (AFR) AF: 0.217 AC: 6798 AN: 31368

American (AMR) AF: 0.266 AC: 9209 AN: 34562

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2680 AN: 24758

East Asian (EAS) AF: 0.395 AC: 14144 AN: 35778

South Asian (SAS) AF: 0.196 AC: 15281 AN: 78018

European-Finnish (FIN) AF: 0.128 AC: 4392 AN: 34426

Middle Eastern (MID) AF: 0.0815 AC: 328 AN: 4024

European-Non Finnish (NFE) AF: 0.173 AC: 185351 AN: 1071130

Other (OTH) AF: 0.181 AC: 10353 AN: 57148

GnomAD4 genome AF: 0.181 AC: 27559 AN: 152198 Hom.: 2653 Cov.: 33 AF XY: 0.181 AC XY: 13454 AN XY: 74416

African (AFR) AF: 0.216 AC: 8951 AN: 41524

American (AMR) AF: 0.204 AC: 3120 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 397 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1702 AN: 5152

South Asian (SAS) AF: 0.200 AC: 963 AN: 4826

European-Finnish (FIN) AF: 0.119 AC: 1264 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10753 AN: 68000

Other (OTH) AF: 0.164 AC: 347 AN: 2114

Alfa AF: 0.172 Hom.: 784

Bravo AF: 0.193

Asia WGS AF: 0.247 AC: 856 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Junctional epidermolysis bullosa (1)
-	-	1	Junctional epidermolysis bullosa gravis of Herlitz (1)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.7
PromoterAI		0.023	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2276542; hg19: chr1-183155399; COSMIC: COSV51459231; COSMIC: COSV51459231;