rs201853235

Positions:

• chr6-129438641-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000426.4(LAMA2):​c.5969-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,466,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: LAMA2 NM_000426.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008116
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.467

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-129438641-C-T is Benign according to our data. Variant chr6-129438641-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 543882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129438641-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.5969-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.5969-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.5969-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000617695.5	c.5969-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000481744
LAMA2	ENST00000618192.5	c.6233-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000480802	P1

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 81 AN: 151192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000857

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000237 AC: 59 AN: 249358 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 134930

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000276 AC: 363 AN: 1315008 Hom.: 0 Cov.: 19 AF XY: 0.000272 AC XY: 180 AN XY: 662336

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000772

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.000271

GnomAD4 genome AF: 0.000535 AC: 81 AN: 151308 Hom.: 0 Cov.: 32 AF XY: 0.000663 AC XY: 49 AN XY: 73898

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.000856

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

LAMA2-related muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.4
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.0040
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: rs201853235; hg19: chr6-129759786; COSMIC: COSV70338346; COSMIC: COSV70338346;