6-129291619-C-T

Variant names:

• chr6-129291619-C-T
• rs138018456
• NM_000426.4:c.2755C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000426.4(LAMA2):​c.2755C>T​(p.Arg919Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,612,964 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R919G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (4 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:2
• Conservation: PhyloP100: 1.00
• Publications: 1 publications found

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]

LAMA2 Gene-Disease associations (from GenCC):

• congenital merosin-deficient muscular dystrophy 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• LAMA2-related muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal recessive 23

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02902162).
• BP6: Variant 6-129291619-C-T is Benign according to our data. Variant chr6-129291619-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 477457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000152 (222/1460650) while in subpopulation AFR AF = 0.00517 (173/33434). AF 95% confidence interval is 0.00454. There are 4 homozygotes in GnomAdExome4. There are 91 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.2755C>T	p.Arg919Cys	missense	Exon 20 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.2755C>T	p.Arg919Cys	missense	Exon 20 of 64	NP_001073291.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.2755C>T	p.Arg919Cys	missense	Exon 20 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.2755C>T	p.Arg919Cys	missense	Exon 20 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.2755C>T	p.Arg919Cys	missense	Exon 20 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000298 AC: 75 AN: 251358 AF XY: 0.000221

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1460650 Hom.: 4 Cov.: 30 AF XY: 0.000125 AC XY: 91 AN XY: 726726

African (AFR) AF: 0.00517 AC: 173 AN: 33434

American (AMR) AF: 0.000134 AC: 6 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86214

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53412

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110948

Other (OTH) AF: 0.000298 AC: 18 AN: 60356

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74496

African (AFR) AF: 0.00341 AC: 142 AN: 41584

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000948

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:1

Dec 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

LAMA2-related muscular dystrophy Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.089
Eigen_PC	Benign	0.00083
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.0
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Benign	0.044	D
Polyphen		0.98	D
Vest4		0.43
MVP		0.81
MPC		0.38
ClinPred		0.077	T
GERP RS		4.0
Varity_R		0.32
gMVP		0.42
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs138018456; hg19: chr6-129612764;