rs202247790

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000426.4(LAMA2):​c.2049_2050delAG​(p.Arg683SerfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.000145 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17U:1O:1

Conservation

PhyloP100: 4.44
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-129252243-AAG-A is Pathogenic according to our data. Variant chr6-129252243-AAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129252243-AAG-A is described in Lovd as [Pathogenic]. Variant chr6-129252243-AAG-A is described in Lovd as [Likely_pathogenic]. Variant chr6-129252243-AAG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMA2NM_000426.4 linkc.2049_2050delAG p.Arg683SerfsTer21 frameshift_variant Exon 14 of 65 ENST00000421865.3 NP_000417.3
LAMA2NM_001079823.2 linkc.2049_2050delAG p.Arg683SerfsTer21 frameshift_variant Exon 14 of 64 NP_001073291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMA2ENST00000421865.3 linkc.2049_2050delAG p.Arg683SerfsTer21 frameshift_variant Exon 14 of 65 5 NM_000426.4 ENSP00000400365.2 P24043
LAMA2ENST00000618192.5 linkc.2049_2050delAG p.Arg683SerfsTer21 frameshift_variant Exon 14 of 66 5 ENSP00000480802.2 A0A087WX80
LAMA2ENST00000617695.5 linkc.2049_2050delAG p.Arg683SerfsTer21 frameshift_variant Exon 14 of 64 5 ENSP00000481744.2 A0A087WYF1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000119
AC:
30
AN:
251274
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000151
AC:
220
AN:
1461760
Hom.:
0
AF XY:
0.000139
AC XY:
101
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000182
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000304
Hom.:
0
Bravo
AF:
0.0000907
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:9Other:1
Mar 13, 2019
Breda Genetics srl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant c.2045_2046delAG (p.Arg683Serfs*21) in the LAMA2 gene is reported as pathogenic for merosin deficient congenital muscular dystrophy in ClinVar (Variation ID: 38340) and as effect unknown in the Whole Genome datasets LAMA2 LOVD database v.3.0 (genomic variant: #0000691061). This variant creates a shift in the reading frame which is predicted to result in a premature stop codon 21 amino acids downstream and is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.0001 in gnomAD exomes, 0.0001 in gnomAD genomes and 0.0002 in NHLI Exome Sequencing Project (ESP), with no homozygous individuals reported. This variant – also known in the literature as c.2049_2050del or Lys682LysfsX22 – is one of the most frequently reported pathogenic variant in the LAMA2 gene, being identified in several individuals affected by congenital muscular dystrophy (e.g. PMIDs: 9541105, 27854218, 25544356, 30055037). -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2. -

Mar 01, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 02, 2021
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000116, PM2). The variant has been reported as pathogenic (ClinVar VCV000038340.19). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 09, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Apr 29, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 03, 2017
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 17, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:5
Nov 18, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 08, 2013
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 31, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP4, PM2, PM3_strong, PS4_moderate, PVS1 -

Aug 05, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed multiple times with a second pathogenic variant in unrelated individuals with merosin-deficient congenital muscular dystrophy (PMID: 9541105, 25544356, 24611677); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28133863, 28877744, 18700894, 25544356, 9541105, 27886618, 27854218, 28804634, 25663498, 31404137, 32827036, 33558818, 32528171, 37476021, 24611677, 11591858, 11369186, 28182637, 30055037, 30301903, 37206914, 36057830, 31066047, 34281576, 20207543, 36945402, 9674786, 37933889) -

Jul 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

LAMA2: PM3:Very Strong, PVS1, PM2 -

LAMA2-related muscular dystrophy Pathogenic:1
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg683Serfs*21) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). This variant is present in population databases (rs751627052, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 9541105, 18700894, 24611677, 25544356). For these reasons, this variant has been classified as Pathogenic. -

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
Jun 17, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
-
Institute of Human Genetics, University of Wuerzburg
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Uncertain:1
Dec 01, 2015
Center for Genetic Medicine Research, Children's National Medical Center
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202247790; hg19: chr6-129573388; API