6-129383155-G-C

Variant names:

• chr6-129383155-G-C
• rs373997222
• NM_000426.4:c.4993G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000426.4(LAMA2):​c.4993G>C​(p.Gly1665Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1665G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.06
• 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)

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 (MetaRNN=0.21916068).
• BP6: Variant 6-129383155-G-C is Benign according to our data. Variant chr6-129383155-G-C is described in CliVar as Benign. Clinvar id is 2832077.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-129383155-G-C is described in CliVar as Benign. Clinvar id is 2832077.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-129383155-G-C is described in CliVar as Benign. Clinvar id is 2832077.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-129383155-G-C is described in CliVar as Benign. Clinvar id is 2832077.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-129383155-G-C is described in CliVar as Benign. Clinvar id is 2832077.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.4993G>C	p.Gly1665Arg	missense_variant	Exon 35 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.4993G>C	p.Gly1665Arg	missense_variant	Exon 35 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.4993G>C	p.Gly1665Arg	missense_variant	Exon 35 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.5257G>C	p.Gly1753Arg	missense_variant	Exon 36 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.4993G>C	p.Gly1665Arg	missense_variant	Exon 35 of 64	5		ENSP00000481744.2
LAMA2	ENST00000687590.1	n.1413G>C		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LAMA2-related muscular dystrophy Benign:1

Feb 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	.;.;L
PhyloP100		4.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	.;.;N
REVEL	Benign	0.082
Sift	Benign	0.31	.;.;T
Polyphen		0.018	.;.;B
Vest4		0.21
MutPred		0.63		Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);
MVP		0.49
MPC		0.12
ClinPred		0.76	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.50
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs373997222; hg19: chr6-129704300;