rs12193446

Variant names:

• chr6-129498893-A-G
• rs12193446
• NM_000426.4:c.8245-3766A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000426.4(LAMA2):​c.8245-3766A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 152,210 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.063 (424 hom., cov: 32)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.957
• Publications: 34 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)

LOC102723409 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

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.8245-3766A>G		intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.8233-3766A>G		intron	N/A	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.8245-3766A>G		intron	N/A	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.8509-3766A>G		intron	N/A	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.8233-3766A>G		intron	N/A	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9631 AN: 152092 Hom.: 424 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.0978

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0933

Gnomad OTH AF: 0.0612

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0633 AC: 9631 AN: 152210 Hom.: 424 Cov.: 32 AF XY: 0.0636 AC XY: 4736 AN XY: 74412

African (AFR) AF: 0.0149 AC: 619 AN: 41546

American (AMR) AF: 0.0480 AC: 734 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 339 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4824

European-Finnish (FIN) AF: 0.119 AC: 1263 AN: 10576

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0933 AC: 6346 AN: 68000

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0792 Hom.: 1125

Bravo AF: 0.0562

Asia WGS AF: 0.0160 AC: 54 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.54
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

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: rs12193446; hg19: chr6-129820038; COSMIC: COSV70343181;