6-129098213-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000426.4(LAMA2):ā€‹c.437C>Gā€‹(p.Ser146Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00014 ( 0 hom., cov: 32)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

6
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.06
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 Uncertain_significance. Variant got 2 ACMG points.

PM1
In a domain Laminin N-terminal (size 251) in uniprot entity LAMA2_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_000426.4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LAMA2NM_000426.4 linkc.437C>G p.Ser146Cys missense_variant 4/65 ENST00000421865.3 NP_000417.3
LAMA2NM_001079823.2 linkc.437C>G p.Ser146Cys missense_variant 4/64 NP_001073291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LAMA2ENST00000421865.3 linkc.437C>G p.Ser146Cys missense_variant 4/655 NM_000426.4 ENSP00000400365.2 P24043

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152086
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000183
AC:
46
AN:
251462
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00119
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000139
AC:
203
AN:
1461526
Hom.:
0
Cov.:
31
AF XY:
0.000160
AC XY:
116
AN XY:
727100
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.000880
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000122
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.000245
Hom.:
0
Bravo
AF:
0.000174
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000181
AC:
22
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 15, 2021Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 15, 2024PP3 -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 21, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 17, 2024Variant summary: LAMA2 c.437C>G (p.Ser146Cys) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy (0.00018 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.437C>G in individuals affected with Laminin Alpha 2-Related Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 543838). Based on the evidence outlined above, the variant was classified as uncertain significance. -
LAMA2-related muscular dystrophy Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.056
.;T;D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.072
D
MetaRNN
Uncertain
0.64
D;D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Pathogenic
3.9
.;.;H
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.5
.;.;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0030
.;.;D
Polyphen
1.0
.;.;D
Vest4
0.79
MVP
0.93
MPC
0.47
ClinPred
0.54
D
GERP RS
5.0
Varity_R
0.86
gMVP
0.85

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: rs143680577; hg19: chr6-129419358; API