6-129260736-G-T

Position:

• chr6-129260736-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000426.4(LAMA2):​c.2122G>T​(p.Ala708Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,456 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 7.34

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2122G>T	p.Ala708Ser	missense_variant	15/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2122G>T	p.Ala708Ser	missense_variant	15/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2122G>T	p.Ala708Ser	missense_variant	15/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5	c.2122G>T	p.Ala708Ser	missense_variant	15/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5	c.2122G>T	p.Ala708Ser	missense_variant	15/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459456 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726186

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.0	.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	.;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.10	.;.;T
Polyphen		0.85	.;.;P
Vest4		0.63
MVP		0.71
MPC		0.45
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.22
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs777765933; hg19: chr6-129581881;