6-128883147-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000426.4(LAMA2):c.-99A>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 0.0334 in 1,202,312 control chromosomes in the GnomAD database, including 785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (82 hom., cov: 32)
  • Exomes 𝑓: 0.034 (703 hom.)
• Consequence: LAMA2 NM_000426.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.807

Genes affected

LAMA2 (HGNC:6482): (laminin subunit alpha 2) Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-128883147-A-G is Benign according to our data. Variant chr6-128883147-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 355234.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.-99A>G		5_prime_UTR_variant	1/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.-99A>G		5_prime_UTR_variant	1/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.-99A>G		5_prime_UTR_variant	1/65	5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4390 AN: 151988 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0503

GnomAD4 exome AF: 0.0340 AC: 35702 AN: 1050206 Hom.: 703 Cov.: 14 AF XY: 0.0340 AC XY: 18006 AN XY: 529348

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.0355

Gnomad4 ASJ exome AF: 0.0537

Gnomad4 EAS exome AF: 0.00289

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.0327

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0289 AC: 4403 AN: 152106 Hom.: 82 Cov.: 32 AF XY: 0.0290 AC XY: 2157 AN XY: 74384

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0345

Gnomad4 ASJ AF: 0.0611

Gnomad4 EAS AF: 0.00389

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0305 Hom.: 12

Bravo AF: 0.0292

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.3
Dann	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111531732; hg19: chr6-129204292;