rs35089085

Variant names:

• chr6-129349331-C-T
• rs35089085
• NM_000426.4:c.4470C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000426.4(LAMA2):​c.4470C>T​(p.Asp1490Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,613,168 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (73 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.00
• Publications: 8 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 6-129349331-C-T is Benign according to our data. Variant chr6-129349331-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00532 (810/152162) while in subpopulation NFE AF = 0.00847 (576/68014). AF 95% confidence interval is 0.0079. There are 4 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.4470C>T	p.Asp1490Asp	synonymous	Exon 31 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.4470C>T	p.Asp1490Asp	synonymous	Exon 31 of 64	NP_001073291.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.4470C>T	p.Asp1490Asp	synonymous	Exon 31 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.4734C>T	p.Asp1578Asp	synonymous	Exon 32 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.4470C>T	p.Asp1490Asp	synonymous	Exon 31 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 812 AN: 152044 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00322

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00557 AC: 1400 AN: 251380 AF XY: 0.00572

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00819

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00849 AC: 12398 AN: 1461006 Hom.: 73 Cov.: 30 AF XY: 0.00817 AC XY: 5941 AN XY: 726822

African (AFR) AF: 0.00120 AC: 40 AN: 33448

American (AMR) AF: 0.00338 AC: 151 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 384 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.00199 AC: 172 AN: 86252

European-Finnish (FIN) AF: 0.00309 AC: 165 AN: 53400

Middle Eastern (MID) AF: 0.00885 AC: 51 AN: 5762

European-Non Finnish (NFE) AF: 0.00966 AC: 10737 AN: 1111322

Other (OTH) AF: 0.0115 AC: 697 AN: 60352

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152162 Hom.: 4 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74398

African (AFR) AF: 0.00212 AC: 88 AN: 41516

American (AMR) AF: 0.00321 AC: 49 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

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

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10586

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00847 AC: 576 AN: 68014

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00820 Hom.: 3

Bravo AF: 0.00530

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00927

EpiControl AF: 0.00848

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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	-0.43
CADD	Benign	3.8
DANN	Benign	0.77
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35089085; hg19: chr6-129670476; COSMIC: COSV104710941;