rs77113162

Variant names:

• chr6-129507559-C-T
• rs77113162
• NM_000426.4:c.8774C>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.8774C>T​(p.Pro2925Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,614,134 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.94
• Publications: 5 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)

ENSG00000226149 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008012801).
• BP6: Variant 6-129507559-C-T is Benign according to our data. Variant chr6-129507559-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385982.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 = 0.00576 (878/152346) while in subpopulation AFR AF = 0.0205 (851/41586). AF 95% confidence interval is 0.0193. There are 10 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.8774C>T	p.Pro2925Leu	missense	Exon 62 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.8762C>T	p.Pro2921Leu	missense	Exon 61 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.8774C>T	p.Pro2925Leu	missense	Exon 62 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.9038C>T	p.Pro3013Leu	missense	Exon 63 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.8762C>T	p.Pro2921Leu	missense	Exon 61 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 876 AN: 152228 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00143 AC: 359 AN: 251310 AF XY: 0.00110

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000564 AC: 824 AN: 1461788 Hom.: 7 Cov.: 32 AF XY: 0.000446 AC XY: 324 AN XY: 727202

African (AFR) AF: 0.0212 AC: 711 AN: 33476

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111926

Other (OTH) AF: 0.00116 AC: 70 AN: 60394

GnomAD4 genome AF: 0.00576 AC: 878 AN: 152346 Hom.: 10 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74492

African (AFR) AF: 0.0205 AC: 851 AN: 41586

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00218 Hom.: 8

Bravo AF: 0.00685

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00176 AC: 214

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	LAMA2-related muscular dystrophy (1)
-	-	1	Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0080	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.90
MPC		0.47
ClinPred		0.037	T
GERP RS		5.3
Varity_R		0.39
gMVP		0.61
Mutation Taster		=80/20	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: rs77113162; hg19: chr6-129828704;