rs41285288

Variant names:

• chr6-129349293-T-A
• rs41285288
• NM_000426.4:c.4437-5T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000426.4(LAMA2):​c.4437-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,611,536 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (73 hom.)
• Consequence: LAMA2 NM_000426.4 splice_region, intron
• Scores: Splicing: ADA: 0.8827
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.73
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-129349293-T-A is Benign according to our data. Variant chr6-129349293-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92958.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 = 0.00547 (833/152300) while in subpopulation NFE AF = 0.00866 (589/68028). AF 95% confidence interval is 0.00808. There are 5 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.4437-5T>A		splice_region intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.4437-5T>A		splice_region intron	N/A	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.4437-5T>A		splice_region intron	N/A	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.4701-5T>A		splice_region intron	N/A	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.4437-5T>A		splice_region intron	N/A	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 835 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00866

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00581 AC: 1459 AN: 251334 AF XY: 0.00608

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00837

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00849 AC: 12394 AN: 1459236 Hom.: 73 Cov.: 30 AF XY: 0.00829 AC XY: 6017 AN XY: 726094

African (AFR) AF: 0.00126 AC: 42 AN: 33426

American (AMR) AF: 0.00335 AC: 150 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 381 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00326 AC: 281 AN: 86226

European-Finnish (FIN) AF: 0.00302 AC: 161 AN: 53380

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5760

European-Non Finnish (NFE) AF: 0.00956 AC: 10607 AN: 1109718

Other (OTH) AF: 0.0117 AC: 704 AN: 60278

GnomAD4 genome AF: 0.00547 AC: 833 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74468

African (AFR) AF: 0.00217 AC: 90 AN: 41564

American (AMR) AF: 0.00314 AC: 48 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

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

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4820

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00866 AC: 589 AN: 68028

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00856 Hom.: 3

Bravo AF: 0.00542

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.00877

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (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
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		1.7
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.060		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: rs41285288; hg19: chr6-129670438;