6-129349348-C-T

Variant names:

• chr6-129349348-C-T
• rs147077184
• NM_000426.4:c.4487C>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.4487C>T​(p.Ala1496Val) variant causes a missense change. The variant allele was found at a frequency of 0.00368 in 1,613,554 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts 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. A1496D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (31 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:12 O:1
• Conservation: PhyloP100: 4.30
• 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=0.032247603).
• BP6: Variant 6-129349348-C-T is Benign according to our data. Variant chr6-129349348-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196660.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00335 (510/152248) while in subpopulation AMR AF = 0.00504 (77/15276). AF 95% confidence interval is 0.00413. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 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.4487C>T	p.Ala1496Val	missense	Exon 31 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.4487C>T	p.Ala1496Val	missense	Exon 31 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.4487C>T	p.Ala1496Val	missense	Exon 31 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.4751C>T	p.Ala1584Val	missense	Exon 32 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.4487C>T	p.Ala1496Val	missense	Exon 31 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00373 AC: 937 AN: 251380 AF XY: 0.00384

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00402

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00371 AC: 5424 AN: 1461306 Hom.: 31 Cov.: 30 AF XY: 0.00364 AC XY: 2649 AN XY: 726982

African (AFR) AF: 0.000747 AC: 25 AN: 33452

American (AMR) AF: 0.00297 AC: 133 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 622 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86254

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53400

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.00374 AC: 4157 AN: 1111578

Other (OTH) AF: 0.00446 AC: 269 AN: 60370

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74440

African (AFR) AF: 0.000650 AC: 27 AN: 41548

American (AMR) AF: 0.00504 AC: 77 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68018

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00377 Hom.: 12

Bravo AF: 0.00342

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00334 AC: 406

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00605

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	2	2	not specified (4)
-	1	1	Merosin deficient congenital muscular dystrophy (3)
1	-	1	Muscular dystrophy, limb-girdle, autosomal recessive 23 (2)
-	1	-	Congenital muscular dystrophy due to partial LAMA2 deficiency (1)
-	-	1	LAMA2-related disorder (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	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.68
MVP		0.75
MPC		0.37
ClinPred		0.015	T
GERP RS		5.1
Varity_R		0.36
gMVP		0.47
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147077184; hg19: chr6-129670493; COSMIC: COSV70352704;