rs1024374408

Variant names:

• chr6-129270767-A-G
• rs1024374408
• NM_000426.4:c.2450+16A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000426.4(LAMA2):​c.2450+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0790
• Publications: 0 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-129270767-A-G is Benign according to our data. Variant chr6-129270767-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 507122.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2450+16A>G		intron_variant	Intron 17 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2450+16A>G		intron_variant	Intron 17 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2450+16A>G		intron_variant	Intron 17 of 64	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.2450+16A>G		intron_variant	Intron 17 of 65	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.2450+16A>G		intron_variant	Intron 17 of 63	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460254 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726508

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60280

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myalgia;C0241005:Elevated circulating creatine kinase concentration;C1850830:Exercise-induced myalgia Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 01, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

LAMA2-related muscular dystrophy Benign:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.62
DANN	Benign	0.71
PhyloP100		0.079

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: rs1024374408; hg19: chr6-129591912;