rs684527

Variant names:

• chr1-183186347-C-A
• rs684527
• NM_005562.3:c.-6C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-183186347-C-A
• chr1-183186347-C-G
• chr1-183186347-C-T

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.-6C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,592,980 control chromosomes in the GnomAD database, including 71,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5797 hom., cov: 33)
  • Exomes 𝑓: 0.30 (65915 hom.)
• Consequence: LAMC2 NM_005562.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.433
• Publications: 12 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=-0.53).
• BP6: Variant 1-183186347-C-A is Benign according to our data. Variant chr1-183186347-C-A is described in ClinVar as Benign. ClinVar VariationId is 293983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 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.-6C>A		5_prime_UTR	Exon 1 of 23	NP_005553.2	Q13753-1
	LAMC2	NM_018891.3		c.-6C>A		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.-6C>A		5_prime_UTR	Exon 1 of 23	ENSP00000264144.4	Q13753-1
	LAMC2	ENST00000493293.5	TSL:1	c.-6C>A		5_prime_UTR	Exon 1 of 22	ENSP00000432063.1	Q13753-2
	LAMC2	ENST00000914499.1		c.-6C>A		5_prime_UTR	Exon 1 of 23	ENSP00000584558.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38975 AN: 151946 Hom.: 5789 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.312 AC: 67186 AN: 215182 AF XY: 0.316

Gnomad AFR exome AF: 0.0999

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.419

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.298 AC: 429504 AN: 1440918 Hom.: 65915 Cov.: 38 AF XY: 0.300 AC XY: 215003 AN XY: 716306

African (AFR) AF: 0.0915 AC: 3052 AN: 33372

American (AMR) AF: 0.328 AC: 14193 AN: 43266

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6047 AN: 25814

East Asian (EAS) AF: 0.388 AC: 15276 AN: 39326

South Asian (SAS) AF: 0.358 AC: 30181 AN: 84302

European-Finnish (FIN) AF: 0.398 AC: 16919 AN: 42512

Middle Eastern (MID) AF: 0.329 AC: 1615 AN: 4906

European-Non Finnish (NFE) AF: 0.293 AC: 324930 AN: 1107672

Other (OTH) AF: 0.289 AC: 17291 AN: 59748

GnomAD4 genome AF: 0.256 AC: 38993 AN: 152062 Hom.: 5797 Cov.: 33 AF XY: 0.266 AC XY: 19736 AN XY: 74298

African (AFR) AF: 0.101 AC: 4193 AN: 41514

American (AMR) AF: 0.295 AC: 4515 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3464

East Asian (EAS) AF: 0.428 AC: 2199 AN: 5142

South Asian (SAS) AF: 0.345 AC: 1664 AN: 4826

European-Finnish (FIN) AF: 0.431 AC: 4542 AN: 10550

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20044 AN: 67970

Other (OTH) AF: 0.279 AC: 590 AN: 2114

Alfa AF: 0.269 Hom.: 1437

Bravo AF: 0.238

Asia WGS AF: 0.378 AC: 1313 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	-0.53
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		0.43
PromoterAI		0.11	Neutral
Mutation Taster		=299/1	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: rs684527; hg19: chr1-183155482;