6-128883150-AGCT-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000426.4(LAMA2):c.-89_-87del variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00143 in 1,227,066 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: LAMA2 NM_000426.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.10

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00665 (1012/152254) while in subpopulation AFR AF= 0.022 (913/41566). AF 95% confidence interval is 0.0208. There are 12 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.-89_-87del		5_prime_UTR_variant	1/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.-89_-87del		5_prime_UTR_variant	1/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.-89_-87del		5_prime_UTR_variant	1/65	5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1010 AN: 152136 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.000690 AC: 742 AN: 1074812 Hom.: 11 AF XY: 0.000645 AC XY: 349 AN XY: 541076

Gnomad4 AFR exome AF: 0.0222

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000113

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00665 AC: 1012 AN: 152254 Hom.: 12 Cov.: 32 AF XY: 0.00658 AC XY: 490 AN XY: 74444

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00463 Hom.: 1

Bravo AF: 0.00773

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital Muscular Dystrophy, LAMA2-related Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs568369254; hg19: chr6-129204295;