6-129280086-C-T

Variant names:

• chr6-129280086-C-T
• rs118147866
• NM_000426.4:c.2476C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000426.4(LAMA2):​c.2476C>T​(p.Arg826Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,613,132 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R826Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (40 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.15
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007732928).
• BP6: Variant 6-129280086-C-T is Benign according to our data. Variant chr6-129280086-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167241.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00529 (806/152228) while in subpopulation NFE AF = 0.00634 (431/68004). AF 95% confidence interval is 0.00584. There are 9 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.2476C>T	p.Arg826Trp	missense	Exon 18 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.2476C>T	p.Arg826Trp	missense	Exon 18 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.2476C>T	p.Arg826Trp	missense	Exon 18 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.2476C>T	p.Arg826Trp	missense	Exon 18 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.2476C>T	p.Arg826Trp	missense	Exon 18 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 806 AN: 152110 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00634

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00533 AC: 1339 AN: 251276 AF XY: 0.00510

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.00603

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00592 AC: 8644 AN: 1460904 Hom.: 40 Cov.: 30 AF XY: 0.00582 AC XY: 4232 AN XY: 726810

African (AFR) AF: 0.000987 AC: 33 AN: 33438

American (AMR) AF: 0.00164 AC: 73 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26120

East Asian (EAS) AF: 0.00118 AC: 47 AN: 39690

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86242

European-Finnish (FIN) AF: 0.0226 AC: 1206 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00619 AC: 6879 AN: 1111276

Other (OTH) AF: 0.00545 AC: 329 AN: 60346

GnomAD4 genome AF: 0.00529 AC: 806 AN: 152228 Hom.: 9 Cov.: 32 AF XY: 0.00585 AC XY: 435 AN XY: 74404

African (AFR) AF: 0.00120 AC: 50 AN: 41546

American (AMR) AF: 0.00190 AC: 29 AN: 15292

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0256 AC: 271 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00634 AC: 431 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00469 Hom.: 3

Bravo AF: 0.00304

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00502 AC: 609

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00486

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.087
Sift	Uncertain	0.021	D
Polyphen		0.027	B
Vest4		0.38
MVP		0.77
MPC		0.095
ClinPred		0.022	T
GERP RS		3.6
Varity_R		0.19
gMVP		0.44
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs118147866; hg19: chr6-129601231; COSMIC: COSV70354251;