rs73775407

Variant names:

• chr6-129440897-C-A
• rs73775407
• NM_000426.4:c.6167C>A

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.6167C>A​(p.Thr2056Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,613,896 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. T2056T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (177 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (165 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.60
• 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: 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)

ENSG00000226149 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017717183).
• BP6: Variant 6-129440897-C-A is Benign according to our data. Variant chr6-129440897-C-A is described in ClinVar as Benign. ClinVar VariationId is 129439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0872 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.6167C>A	p.Thr2056Lys	missense	Exon 43 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.6167C>A	p.Thr2056Lys	missense	Exon 43 of 64	NP_001073291.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.6167C>A	p.Thr2056Lys	missense	Exon 43 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.6431C>A	p.Thr2144Lys	missense	Exon 44 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.6167C>A	p.Thr2056Lys	missense	Exon 43 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3918 AN: 152162 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

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: 0.000323

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00671 AC: 1683 AN: 250744 AF XY: 0.00472

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00267 AC: 3908 AN: 1461616 Hom.: 165 Cov.: 31 AF XY: 0.00232 AC XY: 1687 AN XY: 727128

African (AFR) AF: 0.0950 AC: 3180 AN: 33464

American (AMR) AF: 0.00465 AC: 208 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111826

Other (OTH) AF: 0.00591 AC: 357 AN: 60384

GnomAD4 genome AF: 0.0258 AC: 3933 AN: 152280 Hom.: 177 Cov.: 32 AF XY: 0.0254 AC XY: 1889 AN XY: 74456

African (AFR) AF: 0.0896 AC: 3723 AN: 41546

American (AMR) AF: 0.00954 AC: 146 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68014

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.00981 Hom.: 105

Bravo AF: 0.0292

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00813 AC: 987

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.79
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.29
MPC		0.11
ClinPred		0.0011	T
GERP RS		1.8
Varity_R		0.037
gMVP		0.27
Mutation Taster		=95/5	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: rs73775407; hg19: chr6-129762042;