rs35889149

chr6-129315533-A-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.3613A>G(p.Thr1205Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,614,164 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1205M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.66

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 (MetaRNN=0.0047211647).
• BP6: Variant 6-129315533-A-G is Benign according to our data. Variant chr6-129315533-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129315533-A-G is described in Lovd as [Benign]. Variant chr6-129315533-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1762/152292) while in subpopulation AFR AF= 0.0404 (1679/41564). AF 95% confidence interval is 0.0388. There are 26 homozygotes in gnomad4. There are 825 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.3613A>G	p.Thr1205Ala	missense_variant	25/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.3613A>G	p.Thr1205Ala	missense_variant	25/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.3613A>G	p.Thr1205Ala	missense_variant	25/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.3877A>G	p.Thr1293Ala	missense_variant	26/66	5		P1
LAMA2	ENST00000617695.5	c.3613A>G	p.Thr1205Ala	missense_variant	25/64	5

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1765 AN: 152174 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00313 AC: 786 AN: 251456 Hom.: 8 AF XY: 0.00203 AC XY: 276 AN XY: 135902

Gnomad AFR exome AF: 0.0440

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00117 AC: 1710 AN: 1461872 Hom.: 30 Cov.: 32 AF XY: 0.000972 AC XY: 707 AN XY: 727244

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.0116 AC: 1762 AN: 152292 Hom.: 26 Cov.: 32 AF XY: 0.0111 AC XY: 825 AN XY: 74480

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00249 Hom.: 7

Bravo AF: 0.0137

ESP6500AA AF: 0.0402 AC: 177

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00406 AC: 493

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 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, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of 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

Aug 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	18
Dann	Benign	0.88
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.35	T
Polyphen		0.087	.;.;B
Vest4		0.50
MVP		0.47
MPC		0.10
ClinPred		0.025	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.59

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: rs35889149; hg19: chr6-129636678; COSMIC: COSV99081516;