rs758134778

chr6-129315888-G-Achr6-129315888-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000426.4(LAMA2):c.3862G>A(p.Val1288Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,613,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (2 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.183

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06818333).
• BP6: Variant 6-129315888-G-A is Benign according to our data. Variant chr6-129315888-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 543854.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.3862G>A	p.Val1288Ile	missense_variant	26/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.3862G>A	p.Val1288Ile	missense_variant	26/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.3862G>A	p.Val1288Ile	missense_variant	26/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.4126G>A	p.Val1376Ile	missense_variant	27/66	5		P1
LAMA2	ENST00000617695.5	c.3862G>A	p.Val1288Ile	missense_variant	26/64	5

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251360 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000752 AC: 110 AN: 1461794 Hom.: 2 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

LAMA2-related muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.42
Dann	Benign	0.75
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
Polyphen		0.011	.;.;B
Vest4		0.086
MutPred		0.71		Loss of MoRF binding (P = 0.1132);Loss of MoRF binding (P = 0.1132);Loss of MoRF binding (P = 0.1132);
MVP		0.14
MPC		0.074
ClinPred		0.018	T
GERP RS		-8.2
Varity_R		0.13
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs758134778; hg19: chr6-129637033; COSMIC: COSV70338998;