6-129512482-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000426.4(LAMA2):ā€‹c.8977A>Gā€‹(p.Ile2993Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00032 ( 0 hom., cov: 32)
Exomes š‘“: 0.000023 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.38
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=0.019614786).
BP6
Variant 6-129512482-A-G is Benign according to our data. Variant chr6-129512482-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 543844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LAMA2NM_000426.4 linkuse as main transcriptc.8977A>G p.Ile2993Val missense_variant 63/65 ENST00000421865.3 NP_000417.3
LOC102723409XR_001743860.2 linkuse as main transcriptn.12103-9691T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LAMA2ENST00000421865.3 linkuse as main transcriptc.8977A>G p.Ile2993Val missense_variant 63/655 NM_000426.4 ENSP00000400365
ENST00000665046.1 linkuse as main transcriptn.789-9691T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000322
AC:
49
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00118
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251236
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135762
show subpopulations
Gnomad AFR exome
AF:
0.000923
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461328
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
726988
show subpopulations
Gnomad4 AFR exome
AF:
0.000927
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:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000322
AC:
49
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.00118
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000300
Hom.:
0
Bravo
AF:
0.000298
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 03, 2019- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 24, 2022The c.8977A>G (p.I2993V) alteration is located in exon 63 (coding exon 63) of the LAMA2 gene. This alteration results from a A to G substitution at nucleotide position 8977, causing the isoleucine (I) at amino acid position 2993 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
LAMA2-related muscular dystrophy Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
13
DANN
Benign
0.74
DEOGEN2
Benign
0.0064
.;T;T
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.70
T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.020
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-1.7
.;.;N
MutationTaster
Benign
0.94
N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.37
.;.;N
REVEL
Benign
0.12
Sift
Benign
1.0
.;.;T
Polyphen
0.0
.;.;B
Vest4
0.18
MVP
0.34
MPC
0.075
ClinPred
0.0056
T
GERP RS
0.58
Varity_R
0.034
gMVP
0.12

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: rs145331792; hg19: chr6-129833627; API