rs34505698

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000426.4(LAMA2):​c.3532G>A​(p.Ala1178Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1178V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

3
5
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 9.36
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2941231).
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LAMA2NM_000426.4 linkuse as main transcriptc.3532G>A p.Ala1178Thr missense_variant 24/65 ENST00000421865.3
LAMA2NM_001079823.2 linkuse as main transcriptc.3532G>A p.Ala1178Thr missense_variant 24/64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LAMA2ENST00000421865.3 linkuse as main transcriptc.3532G>A p.Ala1178Thr missense_variant 24/655 NM_000426.4
LAMA2ENST00000618192.5 linkuse as main transcriptc.3796G>A p.Ala1266Thr missense_variant 25/665 P1
LAMA2ENST00000617695.5 linkuse as main transcriptc.3532G>A p.Ala1178Thr missense_variant 24/645

Frequencies

GnomAD3 genomes
AF:
0.000651
AC:
99
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
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:
0.00118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000473
AC:
119
AN:
251476
Hom.:
0
AF XY:
0.000441
AC XY:
60
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000774
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.00121
AC:
1773
AN:
1461744
Hom.:
3
Cov.:
32
AF XY:
0.00118
AC XY:
860
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000537
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.00148
Gnomad4 OTH exome
AF:
0.00142
GnomAD4 genome
AF:
0.000650
AC:
99
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000497
AC XY:
37
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000856
Hom.:
0
Bravo
AF:
0.000714
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00151
AC:
13
ExAC
AF:
0.000395
AC:
48

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 05, 2022In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35710456) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 15, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 29, 2021- -
Uncertain significance, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsOct 05, 2017- -
Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -
Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJul 29, 2019- -
LAMA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 31, 2023The LAMA2 c.3532G>A variant is predicted to result in the amino acid substitution p.Ala1178Thr. This variant was reported as possibly causative variant in compound heterozygous state in an individual with Psychomotor retardation and polyneuropathy (Table S1, Schobers et al 2022. PubMed ID: 35710456). This variant is reported in 0.080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-129635920-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
LAMA2-related muscular dystrophy Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.029
.;T;T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.29
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
.;.;M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.3
.;.;N
REVEL
Benign
0.20
Sift
Benign
0.33
.;.;T
Polyphen
1.0
.;.;D
Vest4
0.79
MVP
0.65
MPC
0.47
ClinPred
0.15
T
GERP RS
5.6
Varity_R
0.21
gMVP
0.66

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: rs34505698; hg19: chr6-129635920; COSMIC: COSV99081521; API