rs113644365

chr6-129505190-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000426.4(LAMA2):c.8548-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,612,462 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (137 hom.)
• Consequence: LAMA2 NM_000426.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004241
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.534

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-129505190-T-C is Benign according to our data. Variant chr6-129505190-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 92991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129505190-T-C is described in Lovd as [Likely_benign]. Variant chr6-129505190-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00833 (1268/152304) while in subpopulation NFE AF= 0.0139 (943/68024). AF 95% confidence interval is 0.0131. There are 11 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.8548-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000421865.3
LOC102723409	XR_001743860.2	n.12103-2399A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.8548-10T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000426.4
	ENST00000665046.1	n.789-2399A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1268 AN: 152186 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00857 AC: 2152 AN: 251122 Hom.: 15 AF XY: 0.00859 AC XY: 1166 AN XY: 135756

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0121 AC: 17636 AN: 1460158 Hom.: 137 Cov.: 30 AF XY: 0.0120 AC XY: 8693 AN XY: 726530

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.00689

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.00672

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.00833 AC: 1268 AN: 152304 Hom.: 11 Cov.: 32 AF XY: 0.00746 AC XY: 556 AN XY: 74482

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00961 Hom.: 2

Bravo AF: 0.00844

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LAMA2: BS1, BS2 -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.0
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.018
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: rs113644365; hg19: chr6-129826335;