6-129475381-G-T

Variant names:

• chr6-129475381-G-T
• rs369558532
• NM_000426.4:c.7440-9G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000426.4(LAMA2):​c.7440-9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000672 in 1,488,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Scores: Splicing: ADA: 0.00001757
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• 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)

ENSG00000226149 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.7440-9G>T		intron_variant	Intron 52 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.7439+2029G>T		intron_variant	Intron 52 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.7440-9G>T		intron_variant	Intron 52 of 64	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.7704-9G>T		intron_variant	Intron 53 of 65	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.7439+2029G>T		intron_variant	Intron 52 of 63	5		ENSP00000481744.2
ENSG00000226149	ENST00000665046.1	n.975+27224C>A		intron_variant	Intron 9 of 9

Frequencies

GnomAD3 genomes AF: 0.00000697 AC: 1 AN: 143406 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000669 AC: 9 AN: 1345368 Hom.: 0 Cov.: 21 AF XY: 0.00000595 AC XY: 4 AN XY: 672740

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30986

American (AMR) AF: 0.00 AC: 0 AN: 43608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24780

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38514

South Asian (SAS) AF: 0.00 AC: 0 AN: 78066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5498

European-Non Finnish (NFE) AF: 0.00000784 AC: 8 AN: 1020442

Other (OTH) AF: 0.00 AC: 0 AN: 56140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000697 AC: 1 AN: 143406 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 69260

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38134

American (AMR) AF: 0.00 AC: 0 AN: 14016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 4978

South Asian (SAS) AF: 0.00 AC: 0 AN: 4322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66094

Other (OTH) AF: 0.00 AC: 0 AN: 1912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.79
DANN	Benign	0.61
PhyloP100		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs369558532; hg19: chr6-129796526;