rs55776770

Variant names:

• chr6-129516175-C-A
• rs55776770
• NM_000426.4:c.9212-15C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-129516175-C-A
• chr6-129516175-C-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.9212-15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,613,500 control chromosomes in the GnomAD database, including 946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (57 hom., cov: 33)
  • Exomes 𝑓: 0.032 (889 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.67
• Publications: 4 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)

ENSG00000226149 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-129516175-C-A is Benign according to our data. Variant chr6-129516175-C-A is described in ClinVar as Benign. ClinVar VariationId is 256095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0227 (3454/152278) while in subpopulation NFE AF = 0.0365 (2480/68026). AF 95% confidence interval is 0.0353. There are 57 homozygotes in GnomAd4. There are 1605 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 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.9212-15C>A		intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.9200-15C>A		intron	N/A	NP_001073291.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.9212-15C>A		intron	N/A	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.9476-15C>A		intron	N/A	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.9200-15C>A		intron	N/A	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3454 AN: 152160 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0233 AC: 5860 AN: 251332 AF XY: 0.0231

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0324 AC: 47412 AN: 1461222 Hom.: 889 Cov.: 32 AF XY: 0.0313 AC XY: 22765 AN XY: 726978

African (AFR) AF: 0.00544 AC: 182 AN: 33480

American (AMR) AF: 0.0149 AC: 667 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 964 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00390 AC: 336 AN: 86254

European-Finnish (FIN) AF: 0.0247 AC: 1320 AN: 53418

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5766

European-Non Finnish (NFE) AF: 0.0379 AC: 42166 AN: 1111374

Other (OTH) AF: 0.0285 AC: 1720 AN: 60388

GnomAD4 genome AF: 0.0227 AC: 3454 AN: 152278 Hom.: 57 Cov.: 33 AF XY: 0.0216 AC XY: 1605 AN XY: 74458

African (AFR) AF: 0.00635 AC: 264 AN: 41556

American (AMR) AF: 0.0177 AC: 270 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0365 AC: 2480 AN: 68026

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0239 Hom.: 19

Bravo AF: 0.0220

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.51
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs55776770; hg19: chr6-129837320;