rs35889149

Variant names:

• chr6-129315533-A-G
• rs35889149
• NM_000426.4:c.3613A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000426.4(LAMA2):​c.3613A>G​(p.Thr1205Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,614,164 control chromosomes in the GnomAD database, including 56 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1205M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.66
• Publications: 7 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047211647).
• BP6: Variant 6-129315533-A-G is Benign according to our data. Variant chr6-129315533-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1762/152292) while in subpopulation AFR AF = 0.0404 (1679/41564). AF 95% confidence interval is 0.0388. There are 26 homozygotes in GnomAd4. There are 825 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.3613A>G	p.Thr1205Ala	missense	Exon 25 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.3613A>G	p.Thr1205Ala	missense	Exon 25 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.3613A>G	p.Thr1205Ala	missense	Exon 25 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.3877A>G	p.Thr1293Ala	missense	Exon 26 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.3613A>G	p.Thr1205Ala	missense	Exon 25 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1765 AN: 152174 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00313 AC: 786 AN: 251456 AF XY: 0.00203

Gnomad AFR exome AF: 0.0440

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00117 AC: 1710 AN: 1461872 Hom.: 30 Cov.: 32 AF XY: 0.000972 AC XY: 707 AN XY: 727244

African (AFR) AF: 0.0427 AC: 1431 AN: 33476

American (AMR) AF: 0.00199 AC: 89 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111996

Other (OTH) AF: 0.00224 AC: 135 AN: 60394

GnomAD4 genome AF: 0.0116 AC: 1762 AN: 152292 Hom.: 26 Cov.: 32 AF XY: 0.0111 AC XY: 825 AN XY: 74480

African (AFR) AF: 0.0404 AC: 1679 AN: 41564

American (AMR) AF: 0.00373 AC: 57 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68010

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00341 Hom.: 16

Bravo AF: 0.0137

ESP6500AA AF: 0.0402 AC: 177

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00406 AC: 493

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Congenital muscular dystrophy due to partial LAMA2 deficiency (1)
-	-	1	LAMA2-related muscular dystrophy (1)
-	-	1	Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.088
Sift	Benign	0.11	T
Polyphen		0.087	B
Vest4		0.50
MVP		0.47
MPC		0.10
ClinPred		0.025	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.59
Mutation Taster		=95/5	polymorphism

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: rs35889149; hg19: chr6-129636678; COSMIC: COSV99081516;