6-129320645-T-C

Position:

chr6-129320645-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000426.4(LAMA2):c.4166T>C(p.Leu1389Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,603,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 5.55

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.4166T>C	p.Leu1389Pro	missense_variant	28/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.4166T>C	p.Leu1389Pro	missense_variant	28/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.4166T>C	p.Leu1389Pro	missense_variant	28/65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 linkuse as main transcript	c.4430T>C	p.Leu1477Pro	missense_variant	29/66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 linkuse as main transcript	c.4166T>C	p.Leu1389Pro	missense_variant	28/64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.0000398

AC:

AN:

251226

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000290

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:

0.0000145

AC:

AN:

1450960

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

722566

show subpopulations

Gnomad4 AFR exome

AF:

0.000511

Gnomad4 AMR exome

AF:

0.0000224

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:

9.07e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000314

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:

0.0000644

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.4166T>C (p.L1389P) alteration is located in exon 28 (coding exon 28) of the LAMA2 gene. This alteration results from a T to C substitution at nucleotide position 4166, causing the leucine (L) at amino acid position 1389 to be replaced by a proline (P). 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.068

.;T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.4

.;.;M

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.1

.;.;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0050

.;.;D

Polyphen

0.99

.;.;D

Vest4

0.58

MVP

0.85

MPC

0.59

ClinPred

0.79

GERP RS

5.3

Varity_R

0.81

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.

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