rs771046502

Variant names:

• chr6-129401345-G-A
• rs771046502
• NM_000426.4:c.5562+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-129401345-G-A
• chr6-129401345-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000426.4(LAMA2):​c.5562+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAMA2 NM_000426.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.26
• Publications: 5 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: Pathogenic. The variant received 14 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 6-129401345-G-A is Pathogenic according to our data. Variant chr6-129401345-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 968246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.5562+5G>A		splice_region_variant, intron_variant	Intron 38 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.5562+5G>A		splice_region_variant, intron_variant	Intron 38 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.5562+5G>A		splice_region_variant, intron_variant	Intron 38 of 64	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.5826+5G>A		splice_region_variant, intron_variant	Intron 39 of 65	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.5562+5G>A		splice_region_variant, intron_variant	Intron 38 of 63	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1378038 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 690296

African (AFR) AF: 0.00 AC: 0 AN: 31472

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25562

East Asian (EAS) AF: 0.00 AC: 0 AN: 39228

South Asian (SAS) AF: 0.00 AC: 0 AN: 84414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036458

Other (OTH) AF: 0.00 AC: 0 AN: 57620

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LAMA2-related muscular dystrophy Pathogenic:2

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 38 of the LAMA2 gene. It does not directly change the encoded amino acid sequence of the LAMA2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of LAMA2-related muscular dystrophy (PMID: 12552556; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS37+5G>A. ClinVar contains an entry for this variant (Variation ID: 968246). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 38, but is expected to preserve the integrity of the reading-frame (PMID: 12552556). This variant disrupts the c.5562+5G nucleotide in the LAMA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9536098, 10611118, 12552556, 17576681, 20207543). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 07, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LAMA2 c.5562+5G>A 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 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing in fibroblast cells from an individual affected with Congenital Muscular Dystrophy (Tezak_2003). The variant was absent in 1530258 control chromosomes. c.5562+5G>A has been observed in heterozygous genotype state in an individual affected with Laminin Alpha 2-Related Dystrophy with the second allele change undetected (Tezak_2003). This variant has also been observed in compound heterozygous state in individual(s) with LAMA2-related muscular dystrophy (Invitae internal data). These reports indicates that this variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 12552556). ClinVar contains an entry for this variant (Variation ID: 968246). 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	-0.38
CADD	Pathogenic	32
DANN	Benign	0.75
PhyloP100		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: 6
DS_DL_spliceai		0.92		Position offset: -5

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

Other links and lift over

dbSNP: rs771046502; hg19: chr6-129722490;