NM_000426.4:c.7760C>T

Variant names:

• chr6-129486484-C-T
• rs2229848
• NM_000426.4:c.7760C>T

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.7760C>T​(p.Ala2587Val) variant causes a missense change. The variant allele was found at a frequency of 0.695 in 1,612,146 control chromosomes in the GnomAD database, including 393,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31327 hom., cov: 32)
  • Exomes 𝑓: 0.70 (362018 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.63
• Publications: 43 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=1.0597179E-5).
• BP6: Variant 6-129486484-C-T is Benign according to our data. Variant chr6-129486484-C-T is described in ClinVar as Benign. ClinVar VariationId is 167247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.714 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.7760C>T	p.Ala2587Val	missense	Exon 56 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.7748C>T	p.Ala2583Val	missense	Exon 55 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.7760C>T	p.Ala2587Val	missense	Exon 56 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.8024C>T	p.Ala2675Val	missense	Exon 57 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.7748C>T	p.Ala2583Val	missense	Exon 55 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95962 AN: 151854 Hom.: 31302 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.654

GnomAD2 exomes AF: 0.672 AC: 168513 AN: 250778 AF XY: 0.677

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.605

Gnomad FIN exome AF: 0.646

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.684

GnomAD4 exome AF: 0.702 AC: 1024939 AN: 1460174 Hom.: 362018 Cov.: 43 AF XY: 0.701 AC XY: 509109 AN XY: 726458

African (AFR) AF: 0.446 AC: 14909 AN: 33434

American (AMR) AF: 0.679 AC: 30366 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 19582 AN: 26118

East Asian (EAS) AF: 0.628 AC: 24890 AN: 39646

South Asian (SAS) AF: 0.650 AC: 56013 AN: 86208

European-Finnish (FIN) AF: 0.641 AC: 34220 AN: 53370

Middle Eastern (MID) AF: 0.699 AC: 4027 AN: 5762

European-Non Finnish (NFE) AF: 0.720 AC: 799642 AN: 1110616

Other (OTH) AF: 0.685 AC: 41290 AN: 60318

GnomAD4 genome AF: 0.632 AC: 96029 AN: 151972 Hom.: 31327 Cov.: 32 AF XY: 0.630 AC XY: 46794 AN XY: 74256

African (AFR) AF: 0.454 AC: 18821 AN: 41430

American (AMR) AF: 0.670 AC: 10235 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2558 AN: 3470

East Asian (EAS) AF: 0.629 AC: 3250 AN: 5168

South Asian (SAS) AF: 0.618 AC: 2977 AN: 4816

European-Finnish (FIN) AF: 0.657 AC: 6924 AN: 10536

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.720 AC: 48911 AN: 67960

Other (OTH) AF: 0.658 AC: 1389 AN: 2112

Alfa AF: 0.693 Hom.: 154225

Bravo AF: 0.625

TwinsUK AF: 0.714 AC: 2648

ALSPAC AF: 0.724 AC: 2791

ESP6500AA AF: 0.467 AC: 2058

ESP6500EA AF: 0.727 AC: 6248

ExAC AF: 0.667 AC: 81020

Asia WGS AF: 0.635 AC: 2208 AN: 3478

EpiCase AF: 0.725

EpiControl AF: 0.727

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.058	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.000011	T
MetaSVM	Uncertain	0.056	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.60
Sift	Benign	0.056	T
Polyphen		1.0	D
Vest4		0.58
MPC		0.45
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.28
gMVP		0.76
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2229848; hg19: chr6-129807629; COSMIC: COSV70342789; COSMIC: COSV70342789;