6-129147080-T-A

Variant names:

• chr6-129147080-T-A
• rs374692035
• NM_000426.4:c.909+32T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000426.4(LAMA2):​c.909+32T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,334,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.545
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-129147080-T-A is Benign according to our data. Variant chr6-129147080-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000117 (138/1182000) while in subpopulation AFR AF = 0.00422 (118/27972). AF 95% confidence interval is 0.0036. There are 0 homozygotes in GnomAdExome4. There are 62 alleles in the male GnomAdExome4 subpopulation. Median coverage is 17. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.909+32T>A		intron_variant	Intron 6 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.909+32T>A		intron_variant	Intron 6 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.909+32T>A		intron_variant	Intron 6 of 64	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes AF: 0.000790 AC: 120 AN: 151962 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000272 AC: 68 AN: 249562 AF XY: 0.000178

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 138 AN: 1182000 Hom.: 0 Cov.: 17 AF XY: 0.000103 AC XY: 62 AN XY: 601604

African (AFR) AF: 0.00422 AC: 118 AN: 27972

American (AMR) AF: 0.000136 AC: 6 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24384

East Asian (EAS) AF: 0.00 AC: 0 AN: 38378

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.000569 AC: 3 AN: 5268

European-Non Finnish (NFE) AF: 0.00000117 AC: 1 AN: 856694

Other (OTH) AF: 0.000157 AC: 8 AN: 51110

GnomAD4 genome AF: 0.000789 AC: 120 AN: 152080 Hom.: 1 Cov.: 32 AF XY: 0.000767 AC XY: 57 AN XY: 74346

African (AFR) AF: 0.00282 AC: 117 AN: 41508

American (AMR) AF: 0.000131 AC: 2 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000975

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.6
DANN	Benign	0.66
PhyloP100		-0.55

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: rs374692035; hg19: chr6-129468225;