chr6-129366251-G-A

Variant names:

• chr6-129366251-G-A
• rs117781224
• NM_000426.4:c.4750G>A

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.4750G>A​(p.Gly1584Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,708 control chromosomes in the GnomAD database, including 802 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (43 hom., cov: 31)
  • Exomes 𝑓: 0.029 (759 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.15
• Publications: 17 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=0.008308321).
• BP6: Variant 6-129366251-G-A is Benign according to our data. Variant chr6-129366251-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2908/151944) while in subpopulation NFE AF = 0.0306 (2081/67942). AF 95% confidence interval is 0.0295. There are 43 homozygotes in GnomAd4. There are 1368 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.4750G>A	p.Gly1584Ser	missense	Exon 33 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.4750G>A	p.Gly1584Ser	missense	Exon 33 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.4750G>A	p.Gly1584Ser	missense	Exon 33 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.5014G>A	p.Gly1672Ser	missense	Exon 34 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.4750G>A	p.Gly1584Ser	missense	Exon 33 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2907 AN: 151826 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00631

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00984

Gnomad FIN AF: 0.00824

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0202

GnomAD2 exomes AF: 0.0195 AC: 4888 AN: 251002 AF XY: 0.0199

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0295 AC: 43091 AN: 1461764 Hom.: 759 Cov.: 32 AF XY: 0.0288 AC XY: 20937 AN XY: 727200

African (AFR) AF: 0.00499 AC: 167 AN: 33480

American (AMR) AF: 0.0119 AC: 533 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 537 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0122 AC: 1055 AN: 86254

European-Finnish (FIN) AF: 0.0126 AC: 674 AN: 53386

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5766

European-Non Finnish (NFE) AF: 0.0345 AC: 38404 AN: 1111930

Other (OTH) AF: 0.0265 AC: 1601 AN: 60390

GnomAD4 genome AF: 0.0191 AC: 2908 AN: 151944 Hom.: 43 Cov.: 31 AF XY: 0.0184 AC XY: 1368 AN XY: 74258

African (AFR) AF: 0.00629 AC: 261 AN: 41468

American (AMR) AF: 0.0206 AC: 314 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0101 AC: 48 AN: 4772

European-Finnish (FIN) AF: 0.00824 AC: 87 AN: 10556

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0306 AC: 2081 AN: 67942

Other (OTH) AF: 0.0199 AC: 42 AN: 2106

Alfa AF: 0.0272 Hom.: 227

Bravo AF: 0.0193

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0330 AC: 284

ExAC AF: 0.0196 AC: 2382

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	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	0.071
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.090
Sift	Benign	0.26	T
Polyphen		0.013	B
Vest4		0.19
MPC		0.088
ClinPred		0.0081	T
GERP RS		3.5
Varity_R		0.038
gMVP		0.73
Mutation Taster		=100/0	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: rs117781224; hg19: chr6-129687396;