rs142083777

Variant names:

• chr6-129050060-C-T
• rs142083777
• NM_000426.4:c.255C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000426.4(LAMA2):​c.255C>T​(p.Ile85Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,614,172 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (5 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.49
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 6-129050060-C-T is Benign according to our data. Variant chr6-129050060-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129436.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.255C>T	p.Ile85Ile	synonymous	Exon 2 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.255C>T	p.Ile85Ile	synonymous	Exon 2 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.255C>T	p.Ile85Ile	synonymous	Exon 2 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.255C>T	p.Ile85Ile	synonymous	Exon 2 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.255C>T	p.Ile85Ile	synonymous	Exon 2 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000533 AC: 134 AN: 251474 AF XY: 0.000544

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000999 AC: 1461 AN: 1461882 Hom.: 5 Cov.: 32 AF XY: 0.000971 AC XY: 706 AN XY: 727240

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000559 AC: 25 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00122 AC: 1360 AN: 1112004

Other (OTH) AF: 0.00109 AC: 66 AN: 60396

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74468

African (AFR) AF: 0.000433 AC: 18 AN: 41560

American (AMR) AF: 0.00301 AC: 46 AN: 15298

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68022

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

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	1	-	Congenital muscular dystrophy due to partial LAMA2 deficiency (1)
-	-	1	LAMA2-related muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		1.5
Mutation Taster		=100/0	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: rs142083777; hg19: chr6-129371205;