rs2244008

Variant names:

• chr6-129491908-A-G
• rs2244008
• NM_000426.4:c.7906A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000426.4(LAMA2):​c.7906A>G​(p.Thr2636Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0722 in 1,605,722 control chromosomes in the GnomAD database, including 4,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2636T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.087 (631 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4181 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.99
• Publications: 30 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Myriad Women’s Health
• 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)

ENSG00000226149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020777285).
• BP6: Variant 6-129491908-A-G is Benign according to our data. Variant chr6-129491908-A-G is described in ClinVar as Benign. ClinVar VariationId is 92989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.7906A>G	p.Thr2636Ala	missense	Exon 57 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.7894A>G	p.Thr2632Ala	missense	Exon 56 of 64	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.7906A>G	p.Thr2636Ala	missense	Exon 57 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000494137.2	TSL:3	c.-30A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	ENSP00000510626.1	A0A8I5KQG5
	LAMA2	ENST00000498257.6	TSL:5	c.-30A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	ENSP00000510533.1	A0A8I5KQG5

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 13305 AN: 152096 Hom.: 634 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0824

GnomAD2 exomes AF: 0.0872 AC: 21834 AN: 250466 AF XY: 0.0862

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0733

Gnomad ASJ exome AF: 0.0855

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0751

GnomAD4 exome AF: 0.0706 AC: 102602 AN: 1453508 Hom.: 4181 Cov.: 31 AF XY: 0.0711 AC XY: 51460 AN XY: 723670

African (AFR) AF: 0.109 AC: 3622 AN: 33270

American (AMR) AF: 0.0704 AC: 3146 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 2230 AN: 26078

East Asian (EAS) AF: 0.163 AC: 6433 AN: 39580

South Asian (SAS) AF: 0.0890 AC: 7659 AN: 86066

European-Finnish (FIN) AF: 0.114 AC: 6104 AN: 53396

Middle Eastern (MID) AF: 0.0601 AC: 346 AN: 5756

European-Non Finnish (NFE) AF: 0.0619 AC: 68356 AN: 1104540

Other (OTH) AF: 0.0783 AC: 4706 AN: 60128

GnomAD4 genome AF: 0.0874 AC: 13302 AN: 152214 Hom.: 631 Cov.: 32 AF XY: 0.0906 AC XY: 6745 AN XY: 74420

African (AFR) AF: 0.113 AC: 4691 AN: 41542

American (AMR) AF: 0.0737 AC: 1127 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3470

East Asian (EAS) AF: 0.164 AC: 848 AN: 5174

South Asian (SAS) AF: 0.112 AC: 539 AN: 4814

European-Finnish (FIN) AF: 0.112 AC: 1189 AN: 10598

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4342 AN: 68006

Other (OTH) AF: 0.0815 AC: 172 AN: 2110

Alfa AF: 0.0723 Hom.: 1461

Bravo AF: 0.0867

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0602 AC: 232

ESP6500AA AF: 0.116 AC: 509

ESP6500EA AF: 0.0630 AC: 542

ExAC AF: 0.0879 AC: 10668

Asia WGS AF: 0.119 AC: 412 AN: 3478

EpiCase AF: 0.0632

EpiControl AF: 0.0636

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Congenital muscular dystrophy due to partial LAMA2 deficiency (1)
-	-	1	LAMA2-related muscular dystrophy (1)
-	-	1	Merosin deficient congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.0057
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.0
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Benign	0.035	D
Polyphen		0.015	B
Vest4		0.082
MPC		0.088
ClinPred		0.035	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.45
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2244008; hg19: chr6-129813053; COSMIC: COSV70340957;