6-129098213-C-T

Position:

chr6-129098213-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_000426.4(LAMA2):c.437C>T(p.Ser146Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S146C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 2.06

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]

LAMA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-129098213-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1431679.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

PP5

Variant 6-129098213-C-T is Pathogenic according to our data. Variant chr6-129098213-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162573.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.437C>T	p.Ser146Phe	missense_variant	4/65	ENST00000421865.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.437C>T	p.Ser146Phe	missense_variant	4/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.437C>T	p.Ser146Phe	missense_variant	4/65	5	NM_000426.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251462

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	Observed in an individual with congenital muscular dystrophy who harbored a second variant on the opposite LAMA2 allele (Oliveira et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26633542, 30055037) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 10, 2021	- -

LAMA2-related muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2021

This sequence change replaces serine with phenylalanine at codon 146 of the LAMA2 protein (p.Ser146Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs143680577, ExAC 0.001%). This missense change has been observed in individual(s) with congenital muscular dystrophy type 1A (PMID: 30055037). ClinVar contains an entry for this variant (Variation ID: 162573). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

.;T;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.9

.;.;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.8

.;.;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

.;.;D

Polyphen

1.0

.;.;D

Vest4

0.89

MutPred

0.71

Loss of disorder (P = 0.041);Loss of disorder (P = 0.041);Loss of disorder (P = 0.041);

MVP

0.93

MPC

0.50

ClinPred

1.0

GERP RS

5.0

Varity_R

0.94

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over