rs186538779

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_000426.4(LAMA2):ā€‹c.2461A>Cā€‹(p.Thr821Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,612,354 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 Likely pathogenic (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T821M) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

8
6
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.62
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 12 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-129280072-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.881
PP5
Variant 6-129280071-A-C is Pathogenic according to our data. Variant chr6-129280071-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129280071-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LAMA2NM_000426.4 linkuse as main transcriptc.2461A>C p.Thr821Pro missense_variant 18/65 ENST00000421865.3 NP_000417.3
LAMA2NM_001079823.2 linkuse as main transcriptc.2461A>C p.Thr821Pro missense_variant 18/64 NP_001073291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LAMA2ENST00000421865.3 linkuse as main transcriptc.2461A>C p.Thr821Pro missense_variant 18/655 NM_000426.4 ENSP00000400365.2 P24043
LAMA2ENST00000618192.5 linkuse as main transcriptc.2461A>C p.Thr821Pro missense_variant 18/665 ENSP00000480802.2 A0A087WX80
LAMA2ENST00000617695.5 linkuse as main transcriptc.2461A>C p.Thr821Pro missense_variant 18/645 ENSP00000481744.2 A0A087WYF1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460218
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726522
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylFeb 15, 2018- -
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 30, 2023This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 821 of the LAMA2 protein (p.Thr821Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LAMA2-related muscular dystrophy (PMID: 24534542, 27858741, 30055037). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242608). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LAMA2 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.065
.;T;T
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.88
D;D;D
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Pathogenic
4.1
.;.;H
PrimateAI
Benign
0.27
T
PROVEAN
Pathogenic
-4.8
.;.;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0020
.;.;D
Polyphen
1.0
.;.;D
Vest4
0.62
MutPred
0.62
Gain of catalytic residue at P820 (P = 0.0126);Gain of catalytic residue at P820 (P = 0.0126);Gain of catalytic residue at P820 (P = 0.0126);
MVP
0.87
MPC
0.53
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.94
gMVP
0.69

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: rs186538779; hg19: chr6-129601216; API