chr6-129143973-G-A

Variant names:

• chr6-129143973-G-A
• rs779975082
• NM_000426.4:c.712G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000426.4(LAMA2):​c.712G>A​(p.Ala238Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,460,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A238D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.94
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Myriad Women’s Health
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.712G>A	p.Ala238Thr	missense	Exon 5 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.712G>A	p.Ala238Thr	missense	Exon 5 of 64	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.712G>A	p.Ala238Thr	missense	Exon 5 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.712G>A	p.Ala238Thr	missense	Exon 5 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.712G>A	p.Ala238Thr	missense	Exon 5 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250812 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000384 AC: 56 AN: 1460168 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 726440

African (AFR) AF: 0.0000299 AC: 1 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1110774

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000710 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	LAMA2-related muscular dystrophy (1)
-	1	-	Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.061	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.91
MPC		0.47
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.88
gMVP		0.78
Mutation Taster		=31/69	disease causing

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: rs779975082; hg19: chr6-129465118;