rs117422805

Positions:

• chr6-129280072-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_000426.4(LAMA2):​c.2462C>T​(p.Thr821Met) variant causes a missense change. The variant allele was found at a frequency of 0.0023 in 1,612,224 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T821P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 3.64

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 Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-129280071-A-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.055688918).
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2462C>T	p.Thr821Met	missense_variant	18/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2462C>T	p.Thr821Met	missense_variant	18/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2462C>T	p.Thr821Met	missense_variant	18/65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.2462C>T	p.Thr821Met	missense_variant	18/66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.2462C>T	p.Thr821Met	missense_variant	18/64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00193 AC: 485 AN: 251274 Hom.: 2 AF XY: 0.00183 AC XY: 248 AN XY: 135788

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00237 AC: 3457 AN: 1459934 Hom.: 10 Cov.: 30 AF XY: 0.00231 AC XY: 1676 AN XY: 726406

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000807

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.00265

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74466

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.00129

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2020	This variant is associated with the following publications: (PMID: 24611677, 24082139, 27896284, 23891399) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	LAMA2: PM5, BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2015	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 29, 2022	Variant summary: LAMA2 c.2462C>T (p.Thr821Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 282674 control chromosomes, predominantly at a frequency of 0.0036 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately two fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.2462C>T has been reported in the literature in at least two homozygous individuals affected with Laminin Alpha 2-Related Dystrophy (example Xiong_2015, Ge_2019, Tan_2021). However, these reports do not provide unequivocal evidence for an association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical-significance assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (VUS n=5, likely benign n=2, benign n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Merosin deficient congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 25, 2017

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	.;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Pathogenic	3.8	.;.;H
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-4.5	.;.;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	.;.;D
Polyphen		1.0	.;.;D
Vest4		0.56
MVP		0.85
MPC		0.47
ClinPred		0.080	T
GERP RS		4.0
Varity_R		0.76
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs117422805; hg19: chr6-129601217;