NM_000426.4:c.-99A>G

Variant names:

• chr6-128883147-A-G
• rs111531732
• NM_000426.4:c.-99A>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.-99A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,202,312 control chromosomes in the GnomAD database, including 785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (82 hom., cov: 32)
  • Exomes 𝑓: 0.034 (703 hom.)
• Consequence: LAMA2 NM_000426.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.807
• Publications: 1 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 (BayesDel_noAF=-0.56).
• BP6: Variant 6-128883147-A-G is Benign according to our data. Variant chr6-128883147-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 355234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0713 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.-99A>G		5_prime_UTR	Exon 1 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.-99A>G		5_prime_UTR	Exon 1 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.-99A>G		5_prime_UTR	Exon 1 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.-99A>G		5_prime_UTR	Exon 1 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.-99A>G		5_prime_UTR	Exon 1 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4390 AN: 151988 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0503

GnomAD4 exome AF: 0.0340 AC: 35702 AN: 1050206 Hom.: 703 Cov.: 14 AF XY: 0.0340 AC XY: 18006 AN XY: 529348

African (AFR) AF: 0.0147 AC: 367 AN: 24926

American (AMR) AF: 0.0355 AC: 1233 AN: 34706

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 1203 AN: 22410

East Asian (EAS) AF: 0.00289 AC: 98 AN: 33888

South Asian (SAS) AF: 0.0320 AC: 2275 AN: 71118

European-Finnish (FIN) AF: 0.0327 AC: 1162 AN: 35552

Middle Eastern (MID) AF: 0.0788 AC: 285 AN: 3618

European-Non Finnish (NFE) AF: 0.0353 AC: 27435 AN: 777560

Other (OTH) AF: 0.0354 AC: 1644 AN: 46428

GnomAD4 genome AF: 0.0289 AC: 4403 AN: 152106 Hom.: 82 Cov.: 32 AF XY: 0.0290 AC XY: 2157 AN XY: 74384

African (AFR) AF: 0.0155 AC: 641 AN: 41460

American (AMR) AF: 0.0345 AC: 527 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.00389 AC: 20 AN: 5144

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4832

European-Finnish (FIN) AF: 0.0313 AC: 332 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0344 AC: 2342 AN: 67988

Other (OTH) AF: 0.0498 AC: 105 AN: 2108

Alfa AF: 0.0305 Hom.: 12

Bravo AF: 0.0292

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital muscular dystrophy due to partial LAMA2 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.3
DANN	Benign	0.79
PhyloP100		-0.81
PromoterAI		0.032	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111531732; hg19: chr6-129204292;