6-129349403-C-T

Variant names:

• chr6-129349403-C-T
• rs17057158
• NM_000426.4:c.4523+19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000426.4(LAMA2):​c.4523+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,573,726 control chromosomes in the GnomAD database, including 4,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (633 hom., cov: 32)
  • Exomes 𝑓: 0.066 (4013 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.418
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-129349403-C-T is Benign according to our data. Variant chr6-129349403-C-T is described in ClinVar as Benign. ClinVar VariationId is 92960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.4523+19C>T		intron_variant	Intron 31 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.4523+19C>T		intron_variant	Intron 31 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.4523+19C>T		intron_variant	Intron 31 of 64	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 12563 AN: 151828 Hom.: 629 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0849

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0577

Gnomad OTH AF: 0.0954

GnomAD2 exomes AF: 0.0891 AC: 22382 AN: 251162 AF XY: 0.0884

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0847

Gnomad EAS exome AF: 0.0313

Gnomad FIN exome AF: 0.0492

Gnomad NFE exome AF: 0.0607

Gnomad OTH exome AF: 0.0882

GnomAD4 exome AF: 0.0659 AC: 93730 AN: 1421780 Hom.: 4013 Cov.: 25 AF XY: 0.0678 AC XY: 48130 AN XY: 709810

African (AFR) AF: 0.116 AC: 3795 AN: 32686

American (AMR) AF: 0.185 AC: 8256 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 2285 AN: 25870

East Asian (EAS) AF: 0.0304 AC: 1201 AN: 39468

South Asian (SAS) AF: 0.131 AC: 11238 AN: 85544

European-Finnish (FIN) AF: 0.0509 AC: 2716 AN: 53320

Middle Eastern (MID) AF: 0.117 AC: 670 AN: 5708

European-Non Finnish (NFE) AF: 0.0548 AC: 58967 AN: 1075542

Other (OTH) AF: 0.0780 AC: 4602 AN: 58982

GnomAD4 genome AF: 0.0829 AC: 12591 AN: 151946 Hom.: 633 Cov.: 32 AF XY: 0.0838 AC XY: 6225 AN XY: 74274

African (AFR) AF: 0.113 AC: 4667 AN: 41436

American (AMR) AF: 0.142 AC: 2160 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 294 AN: 3464

East Asian (EAS) AF: 0.0353 AC: 183 AN: 5178

South Asian (SAS) AF: 0.119 AC: 572 AN: 4798

European-Finnish (FIN) AF: 0.0526 AC: 554 AN: 10524

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0576 AC: 3918 AN: 67974

Other (OTH) AF: 0.0963 AC: 203 AN: 2108

Alfa AF: 0.0717 Hom.: 1412

Bravo AF: 0.0900

Asia WGS AF: 0.105 AC: 365 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Merosin deficient congenital muscular dystrophy Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.17
DANN	Benign	0.60
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17057158; hg19: chr6-129670548;