chr6-129250182-A-AACGTGTTC

Variant names:

• chr6-129250182-A-AACGTGTTC
• rs202247791
• NM_000426.4:c.1854_1861dupACGTGTTC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000426.4(LAMA2):​c.1854_1861dupACGTGTTC​(p.Leu621HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,603,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L621L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LAMA2 NM_000426.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 1.23
• Publications: 4 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-129250182-A-AACGTGTTC is Pathogenic according to our data. Variant chr6-129250182-A-AACGTGTTC is described in ClinVar as Pathogenic. ClinVar VariationId is 38339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.1854_1861dupACGTGTTC	p.Leu621HisfsTer7	frameshift	Exon 13 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.1854_1861dupACGTGTTC	p.Leu621HisfsTer7	frameshift	Exon 13 of 64	NP_001073291.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.1854_1861dupACGTGTTC	p.Leu621HisfsTer7	frameshift	Exon 13 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.1854_1861dupACGTGTTC	p.Leu621HisfsTer7	frameshift	Exon 13 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.1854_1861dupACGTGTTC	p.Leu621HisfsTer7	frameshift	Exon 13 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451638 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722992

African (AFR) AF: 0.00 AC: 0 AN: 33064

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103126

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Merosin deficient congenital muscular dystrophy (3)
2	-	-	Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (2)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	LAMA2-related muscular dystrophy (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs202247791; hg19: chr6-129571327;