dbSNP rs202247792: LAMA2:p.His2627Gln (chr6-129486605-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PS1_ModeratePM2BP4

The NM_000426.4(LAMA2):c.7881T>A(p.His2627Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H2627H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.07

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital merosin-deficient muscular dystrophy 1A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
LAMA2-related muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
muscular dystrophy, limb-girdle, autosomal recessive 23
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

LAMA2 links:

ENSG00000226149 (HGNC:):

ENSG00000226149 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PS1

Transcript NM_000426.4 (LAMA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32134816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LAMA2	NM_000426.4 link	c.7881T>A	p.His2627Gln	missense_variant	Exon 56 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.7869T>A	p.His2623Gln	missense_variant	Exon 55 of 64		NP_001073291.2
LOC124901401	XR_007059767.1 link	n.-131A>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.7881T>A	p.His2627Gln	missense_variant	Exon 56 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111790

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.28

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.015

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.049

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.4

.;.;L

PhyloP100

-1.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.42

.;.;N

REVEL

Uncertain

0.44

Sift

Benign

0.45

.;.;T

Polyphen

0.83

.;.;P

Vest4

0.42

MutPred

0.47

.;.;Loss of sheet (P = 0.0817);

MVP

0.42

MPC

0.29

ClinPred

0.43

GERP RS

-11

Varity_R

0.098

gMVP

0.53

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over