6-129252129-C-G

Variant names:

• chr6-129252129-C-G
• rs35879899
• NM_000426.4:c.1930C>G

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.1930C>G​(p.His644Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,452 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0083 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (19 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.323
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Myriad Women’s Health
• 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=0.0055108666).
• BP6: Variant 6-129252129-C-G is Benign according to our data. Variant chr6-129252129-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00829 (1262/152144) while in subpopulation AFR AF = 0.0295 (1224/41480). AF 95% confidence interval is 0.0281. There are 19 homozygotes in GnomAd4. There are 578 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.1930C>G	p.His644Asp	missense	Exon 14 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.1930C>G	p.His644Asp	missense	Exon 14 of 64	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.1930C>G	p.His644Asp	missense	Exon 14 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.1930C>G	p.His644Asp	missense	Exon 14 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.1930C>G	p.His644Asp	missense	Exon 14 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1263 AN: 152026 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000588

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00217 AC: 544 AN: 251118 AF XY: 0.00157

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000803 AC: 1174 AN: 1461308 Hom.: 19 Cov.: 30 AF XY: 0.000696 AC XY: 506 AN XY: 727012

African (AFR) AF: 0.0306 AC: 1025 AN: 33456

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111590

Other (OTH) AF: 0.00116 AC: 70 AN: 60382

GnomAD4 genome AF: 0.00829 AC: 1262 AN: 152144 Hom.: 19 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74386

African (AFR) AF: 0.0295 AC: 1224 AN: 41480

American (AMR) AF: 0.00111 AC: 17 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00140 Hom.: 4

Bravo AF: 0.00937

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00290 AC: 352

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Congenital muscular dystrophy due to partial LAMA2 deficiency (1)
-	-	1	LAMA2-related muscular dystrophy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.32
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.41
MPC		0.12
ClinPred		0.0036	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.69
Mutation Taster		=92/8	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: rs35879899; hg19: chr6-129573274;