rs902373

Variant names:

• chr6-129300910-A-G
• rs902373
• NM_000426.4:c.3174+38A>G

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.3174+38A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,608,002 control chromosomes in the GnomAD database, including 144,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10583 hom., cov: 32)
  • Exomes 𝑓: 0.42 (134031 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.300
• Publications: 6 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-129300910-A-G is Benign according to our data. Variant chr6-129300910-A-G is described in ClinVar as Benign. ClinVar VariationId is 256064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.445 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.3174+38A>G		intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.3174+38A>G		intron	N/A	NP_001073291.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.3174+38A>G		intron	N/A	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.3438+38A>G		intron	N/A	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.3174+38A>G		intron	N/A	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52307 AN: 151882 Hom.: 10587 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.396 AC: 99290 AN: 250836 AF XY: 0.406

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.423 AC: 615939 AN: 1456002 Hom.: 134031 Cov.: 31 AF XY: 0.426 AC XY: 308633 AN XY: 724740

African (AFR) AF: 0.129 AC: 4318 AN: 33390

American (AMR) AF: 0.302 AC: 13488 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 14570 AN: 26070

East Asian (EAS) AF: 0.277 AC: 10963 AN: 39640

South Asian (SAS) AF: 0.438 AC: 37742 AN: 86112

European-Finnish (FIN) AF: 0.384 AC: 20486 AN: 53396

Middle Eastern (MID) AF: 0.485 AC: 2788 AN: 5754

European-Non Finnish (NFE) AF: 0.440 AC: 486985 AN: 1106784

Other (OTH) AF: 0.409 AC: 24599 AN: 60156

GnomAD4 genome AF: 0.344 AC: 52314 AN: 152000 Hom.: 10583 Cov.: 32 AF XY: 0.342 AC XY: 25426 AN XY: 74290

African (AFR) AF: 0.143 AC: 5912 AN: 41486

American (AMR) AF: 0.327 AC: 4991 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1983 AN: 3468

East Asian (EAS) AF: 0.283 AC: 1460 AN: 5164

South Asian (SAS) AF: 0.415 AC: 2004 AN: 4830

European-Finnish (FIN) AF: 0.383 AC: 4036 AN: 10540

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.449 AC: 30496 AN: 67944

Other (OTH) AF: 0.385 AC: 811 AN: 2106

Alfa AF: 0.424 Hom.: 5886

Bravo AF: 0.331

Asia WGS AF: 0.403 AC: 1400 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Merosin deficient congenital muscular dystrophy (1)
-	-	1	Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.28
DANN	Benign	0.71
PhyloP100		-0.30
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: rs902373; hg19: chr6-129622055; COSMIC: COSV70342530; COSMIC: COSV70342530;