chr6-129383155-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000426.4(LAMA2):​c.4993G>T​(p.Gly1665*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G1665G) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

LAMA2
NM_000426.4 stop_gained

Scores

4
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.06

Publications

5 publications found
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 6-129383155-G-T is Pathogenic according to our data. Variant chr6-129383155-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 984089.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMA2NM_000426.4 linkc.4993G>T p.Gly1665* stop_gained Exon 35 of 65 ENST00000421865.3 NP_000417.3
LAMA2NM_001079823.2 linkc.4993G>T p.Gly1665* stop_gained Exon 35 of 64 NP_001073291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMA2ENST00000421865.3 linkc.4993G>T p.Gly1665* stop_gained Exon 35 of 65 5 NM_000426.4 ENSP00000400365.2 P24043
LAMA2ENST00000618192.5 linkc.5257G>T p.Gly1753* stop_gained Exon 36 of 66 5 ENSP00000480802.2 A0A087WX80
LAMA2ENST00000617695.5 linkc.4993G>T p.Gly1665* stop_gained Exon 35 of 64 5 ENSP00000481744.2 A0A087WYF1
LAMA2ENST00000687590.1 linkn.1413G>T non_coding_transcript_exon_variant Exon 3 of 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
Jan 28, 2019
Myriad Genetics, Inc.
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
43
DANN
Uncertain
0.99
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.93
D
PhyloP100
4.1
Vest4
0.82
GERP RS
5.7
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.20
Position offset: -33

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

Publications

Other links and lift over

dbSNP: rs373997222; hg19: chr6-129704300; API