rs374403765

Variant names:

• chr6-128883247-T-A
• NM_000426.4:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-128883247-T-A
• chr6-128883247-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000426.4(LAMA2):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LAMA2 NM_000426.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 65 codons. Genomic position: 129049998. Lost 0.021 part of the original CDS.
• PS1: Another start lost variant in NM_000426.4 (LAMA2) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2T>A	p.Met1?	start_lost	Exon 1 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2T>A	p.Met1?	start_lost	Exon 1 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2T>A	p.Met1?	start_lost	Exon 1 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399828 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.014	.;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.96	T
PROVEAN	Benign	-1.1	.;.;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	.;.;D
Polyphen		0.93	.;.;P
Vest4		0.87
MutPred		0.99		Gain of ubiquitination at M1 (P = 0.0203);Gain of ubiquitination at M1 (P = 0.0203);Gain of ubiquitination at M1 (P = 0.0203);
MVP		0.81
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.78

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-129204392;