rs1047569721

Variant names:

• chr6-129328412-G-A
• rs1047569721
• NM_000426.4:c.4311G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000426.4(LAMA2):​c.4311G>A​(p.Gln1437Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000131 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: LAMA2 NM_000426.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.21
• Publications: 2 publications found

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]

LAMA2 Gene-Disease associations (from GenCC):

• congenital merosin-deficient muscular dystrophy 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• LAMA2-related muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal recessive 23

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-129328412-G-A is Pathogenic according to our data. Variant chr6-129328412-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477472.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.4311G>A	p.Gln1437Gln	splice_region_variant, synonymous_variant	Exon 29 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.4311G>A	p.Gln1437Gln	splice_region_variant, synonymous_variant	Exon 29 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.4311G>A	p.Gln1437Gln	splice_region_variant, synonymous_variant	Exon 29 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.4575G>A	p.Gln1525Gln	splice_region_variant, synonymous_variant	Exon 30 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.4311G>A	p.Gln1437Gln	splice_region_variant, synonymous_variant	Exon 29 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

LAMA2-related muscular dystrophy Pathogenic:1 Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1437 of the LAMA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LAMA2 protein. This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with congenital muscular dystrophy (PMID: 28182637). ClinVar contains an entry for this variant (Variation ID: 477472). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 28182637). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LAMA2 c.4311G>A (p.Gln1437Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence confirming that this variant affects mRNA splicing (Liang_2017). The variant allele was found at a frequency of 1.3e-05 in 150988 control chromosomes (gnomAD v.3.1.2). c.4311G>A has been reported in the literature in at least one compound heterozygous individual affected with Congenital Muscular Dystrophy (Liang_2017). These data do not allow any conclusion about variant significance. The following publication has been ascertained in the context of this evaluation (PMID: 28182637). One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.86
PhyloP100		5.2
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: 28
DS_DL_spliceai		0.97		Position offset: 0

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

Other links and lift over

dbSNP: rs1047569721; hg19: chr6-129649557;