rs1554287445

Variant names:

• chr6-129393253-G-C
• rs1554287445
• NM_000426.4:c.5443G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000426.4(LAMA2):​c.5443G>C​(p.Glu1815Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense, splice_region
• Scores: Splicing: ADA: 0.002030
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 7.21
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.5443G>C	p.Glu1815Gln	missense_variant, splice_region_variant	Exon 37 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.5443G>C	p.Glu1815Gln	missense_variant, splice_region_variant	Exon 37 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.5443G>C	p.Glu1815Gln	missense_variant, splice_region_variant	Exon 37 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.5707G>C	p.Glu1903Gln	missense_variant, splice_region_variant	Exon 38 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.5443G>C	p.Glu1815Gln	missense_variant, splice_region_variant	Exon 37 of 64	5		ENSP00000481744.2
LAMA2	ENST00000687590.1	n.1863G>C		non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458776 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725894

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109328

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	.;.;M
PhyloP100		7.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.22	.;.;N
REVEL	Benign	0.21
Sift	Benign	0.36	.;.;T
Polyphen		1.0	.;.;D
Vest4		0.52
MutPred		0.58		Gain of MoRF binding (P = 0.0191);Gain of MoRF binding (P = 0.0191);Gain of MoRF binding (P = 0.0191);
MVP		0.61
MPC		0.37
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.21
gMVP		0.24
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs1554287445; hg19: chr6-129714398;