NM_000426.4:c.4750G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000426.4(LAMA2):​c.4750G>A​(p.Gly1584Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,708 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 43 hom., cov: 31)
Exomes 𝑓: 0.029 ( 759 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

1
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.15
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008308321).
BP6
Variant 6-129366251-G-A is Benign according to our data. Variant chr6-129366251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129366251-G-A is described in Lovd as [Pathogenic]. Variant chr6-129366251-G-A is described in Lovd as [Likely_benign]. Variant chr6-129366251-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2908/151944) while in subpopulation NFE AF= 0.0306 (2081/67942). AF 95% confidence interval is 0.0295. There are 43 homozygotes in gnomad4. There are 1368 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMA2NM_000426.4 linkc.4750G>A p.Gly1584Ser missense_variant Exon 33 of 65 ENST00000421865.3 NP_000417.3
LAMA2NM_001079823.2 linkc.4750G>A p.Gly1584Ser missense_variant Exon 33 of 64 NP_001073291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMA2ENST00000421865.3 linkc.4750G>A p.Gly1584Ser missense_variant Exon 33 of 65 5 NM_000426.4 ENSP00000400365.2 P24043

Frequencies

GnomAD3 genomes
AF:
0.0191
AC:
2907
AN:
151826
Hom.:
44
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00631
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0205
Gnomad ASJ
AF:
0.0202
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00984
Gnomad FIN
AF:
0.00824
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0306
Gnomad OTH
AF:
0.0202
GnomAD3 exomes
AF:
0.0195
AC:
4888
AN:
251002
Hom.:
75
AF XY:
0.0199
AC XY:
2701
AN XY:
135632
show subpopulations
Gnomad AFR exome
AF:
0.00578
Gnomad AMR exome
AF:
0.0114
Gnomad ASJ exome
AF:
0.0230
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0123
Gnomad FIN exome
AF:
0.0115
Gnomad NFE exome
AF:
0.0302
Gnomad OTH exome
AF:
0.0199
GnomAD4 exome
AF:
0.0295
AC:
43091
AN:
1461764
Hom.:
759
Cov.:
32
AF XY:
0.0288
AC XY:
20937
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00499
Gnomad4 AMR exome
AF:
0.0119
Gnomad4 ASJ exome
AF:
0.0205
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0122
Gnomad4 FIN exome
AF:
0.0126
Gnomad4 NFE exome
AF:
0.0345
Gnomad4 OTH exome
AF:
0.0265
GnomAD4 genome
AF:
0.0191
AC:
2908
AN:
151944
Hom.:
43
Cov.:
31
AF XY:
0.0184
AC XY:
1368
AN XY:
74258
show subpopulations
Gnomad4 AFR
AF:
0.00629
Gnomad4 AMR
AF:
0.0206
Gnomad4 ASJ
AF:
0.0202
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.0101
Gnomad4 FIN
AF:
0.00824
Gnomad4 NFE
AF:
0.0306
Gnomad4 OTH
AF:
0.0199
Alfa
AF:
0.0279
Hom.:
124
Bravo
AF:
0.0193
TwinsUK
AF:
0.0337
AC:
125
ALSPAC
AF:
0.0330
AC:
127
ESP6500AA
AF:
0.00840
AC:
37
ESP6500EA
AF:
0.0330
AC:
284
ExAC
AF:
0.0196
AC:
2382
Asia WGS
AF:
0.00289
AC:
10
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 08, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 10, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 02, 2012
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:5
-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

LAMA2: BP4, BS1, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.68
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
12
DANN
Uncertain
0.98
DEOGEN2
Benign
0.012
.;T;T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.62
T;T;T
MetaRNN
Benign
0.0083
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.97
.;.;L
PrimateAI
Benign
0.34
T
PROVEAN
Benign
0.080
.;.;N
REVEL
Benign
0.090
Sift
Benign
0.26
.;.;T
Polyphen
0.013
.;.;B
Vest4
0.19
MPC
0.088
ClinPred
0.0081
T
GERP RS
3.5
Varity_R
0.038
gMVP
0.73

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: rs117781224; hg19: chr6-129687396; API