rs17741922

Positions:

• chr6-129315461-T-G

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.3556-15T>G 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 0.0066 in 1,613,290 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (95 hom.)
• Consequence: LAMA2 NM_000426.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0990

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-129315461-T-G is Benign according to our data. Variant chr6-129315461-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 92953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129315461-T-G is described in Lovd as [Likely_benign]. Variant chr6-129315461-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.005 (761/152314) while in subpopulation SAS AF= 0.0313 (151/4830). AF 95% confidence interval is 0.0272. There are 8 homozygotes in gnomad4. There are 415 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.3556-15T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.3556-15T>G		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.3556-15T>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000617695.5	c.3556-15T>G		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000481744
LAMA2	ENST00000618192.5	c.3820-15T>G		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000480802	P1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 760 AN: 152196 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00787 AC: 1979 AN: 251406 Hom.: 24 AF XY: 0.00924 AC XY: 1255 AN XY: 135886

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0262

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00715

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00676 AC: 9879 AN: 1460976 Hom.: 95 Cov.: 31 AF XY: 0.00745 AC XY: 5415 AN XY: 726904

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0262

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00576

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152314 Hom.: 8 Cov.: 32 AF XY: 0.00557 AC XY: 415 AN XY: 74478

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00445 Hom.: 1

Bravo AF: 0.00335

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.3
DANN	Benign	0.58

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: rs17741922; hg19: chr6-129636606;