6-129267114-G-C

Variant names:

• chr6-129267114-G-C
• rs192317605
• NM_000426.4:c.2217G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000426.4(LAMA2):​c.2217G>C​(p.Trp739Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,358 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2217G>C	p.Trp739Cys	missense_variant	Exon 16 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2217G>C	p.Trp739Cys	missense_variant	Exon 16 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2217G>C	p.Trp739Cys	missense_variant	Exon 16 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.2217G>C	p.Trp739Cys	missense_variant	Exon 16 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.2217G>C	p.Trp739Cys	missense_variant	Exon 16 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251002 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456358 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	.;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.020	.;.;D
Polyphen		1.0	.;.;D
Vest4		0.77
MutPred		0.65		Loss of catalytic residue at W739 (P = 0.0034);Loss of catalytic residue at W739 (P = 0.0034);Loss of catalytic residue at W739 (P = 0.0034);
MVP		0.62
MPC		0.56
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.18
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs192317605; hg19: chr6-129588259;