rs778059153
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000426.4(LAMA2):āc.2089A>Gā(p.Ile697Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,612,204 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000048 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 missense
NM_000426.4 missense
Scores
1
12
Clinical Significance
Conservation
PhyloP100: 6.06
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.2089A>G | p.Ile697Val | missense_variant | 14/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.2089A>G | p.Ile697Val | missense_variant | 14/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.2089A>G | p.Ile697Val | missense_variant | 14/65 | 5 | NM_000426.4 | ||
LAMA2 | ENST00000618192.5 | c.2089A>G | p.Ile697Val | missense_variant | 14/66 | 5 | P1 | ||
LAMA2 | ENST00000617695.5 | c.2089A>G | p.Ile697Val | missense_variant | 14/64 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460000Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726444
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 03, 2023 | Variant summary: LAMA2 c.2089A>G (p.Ile697Val) results in a conservative amino acid change located in the Laminin IV domain (IPR000034) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250700 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2089A>G has been reported in the literature in an individual who was homozygous for this variant and likely benign variant p.Gly1584Ser, affected with laminin alpha-2 deficiency (MDC1A) (example: Beytia_2014). Muscle biopsy from this patient showed complete absence of laminin alpha-2 and dystrophic myopathy by haematoxyline eosin staining. The following publication has been ascertained in the context of this evaluation (PMID: 24225367). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Merosin deficient congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 17, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 26, 2022 | The c.2089A>G (p.I697V) alteration is located in exon 14 (coding exon 14) of the LAMA2 gene. This alteration results from a A to G substitution at nucleotide position 2089, causing the isoleucine (I) at amino acid position 697 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Benign
T
Polyphen
0.061
.;.;B
Vest4
MutPred
Gain of MoRF binding (P = 0.2496);Gain of MoRF binding (P = 0.2496);Gain of MoRF binding (P = 0.2496);
MVP
MPC
0.081
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at