6-129250202-A-T

Position:

• chr6-129250202-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000426.4(LAMA2):​c.1873A>T​(p.Ile625Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31854555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.1873A>T	p.Ile625Phe	missense_variant	13/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.1873A>T	p.Ile625Phe	missense_variant	13/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.1873A>T	p.Ile625Phe	missense_variant	13/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5	c.1873A>T	p.Ile625Phe	missense_variant	13/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5	c.1873A>T	p.Ile625Phe	missense_variant	13/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74286

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.056	.;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	.;.;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.4	.;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	.;.;D
Polyphen		0.17	.;.;B
Vest4		0.30
MutPred		0.71		Gain of catalytic residue at I625 (P = 0.1189);Gain of catalytic residue at I625 (P = 0.1189);Gain of catalytic residue at I625 (P = 0.1189);
MVP		0.20
MPC		0.24
ClinPred		0.92	D
GERP RS		-4.8
Varity_R		0.50
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs141658354; hg19: chr6-129571347;