chr6-129250263-A-C

Variant names:

• chr6-129250263-A-C
• rs116773503
• NM_000426.4:c.1884+50A>C

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.1884+50A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,117,852 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (13 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.68
• 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 (BayesDel_noAF=-0.81).
• BP6: Variant 6-129250263-A-C is Benign according to our data. Variant chr6-129250263-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 256055.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 = 0.00721 (1098/152208) while in subpopulation AFR AF = 0.0253 (1051/41522). AF 95% confidence interval is 0.024. There are 5 homozygotes in GnomAd4. There are 507 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.1884+50A>C		intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.1884+50A>C		intron	N/A	NP_001073291.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.1884+50A>C		intron	N/A	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.1884+50A>C		intron	N/A	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.1884+50A>C		intron	N/A	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1093 AN: 152092 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00192 AC: 474 AN: 247036 AF XY: 0.00140

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000757 AC: 731 AN: 965644 Hom.: 13 Cov.: 13 AF XY: 0.000635 AC XY: 319 AN XY: 502304

African (AFR) AF: 0.0252 AC: 574 AN: 22764

American (AMR) AF: 0.00129 AC: 57 AN: 44068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22990

East Asian (EAS) AF: 0.00 AC: 0 AN: 37386

South Asian (SAS) AF: 0.0000525 AC: 4 AN: 76224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49880

Middle Eastern (MID) AF: 0.00166 AC: 8 AN: 4820

European-Non Finnish (NFE) AF: 0.00000905 AC: 6 AN: 663302

Other (OTH) AF: 0.00185 AC: 82 AN: 44210

GnomAD4 genome AF: 0.00721 AC: 1098 AN: 152208 Hom.: 5 Cov.: 32 AF XY: 0.00681 AC XY: 507 AN XY: 74428

African (AFR) AF: 0.0253 AC: 1051 AN: 41522

American (AMR) AF: 0.00229 AC: 35 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00472 Hom.: 3

Bravo AF: 0.00840

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		1.7
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: rs116773503; hg19: chr6-129571408;