rs2306220

Variant names:

• chr6-129190228-T-C
• rs2306220
• NM_000426.4:c.1491T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-129190228-T-C
• chr6-129190228-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000426.4(LAMA2):​c.1491T>C​(p.Cys497Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,580 control chromosomes in the GnomAD database, including 1,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (101 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1036 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.301
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-129190228-T-C is Benign according to our data. Variant chr6-129190228-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.301 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

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.1491T>C	p.Cys497Cys	synonymous	Exon 11 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.1491T>C	p.Cys497Cys	synonymous	Exon 11 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.1491T>C	p.Cys497Cys	synonymous	Exon 11 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.1491T>C	p.Cys497Cys	synonymous	Exon 11 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.1491T>C	p.Cys497Cys	synonymous	Exon 11 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3219 AN: 152192 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0319 AC: 8000 AN: 251138 AF XY: 0.0341

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0202 AC: 29569 AN: 1461270 Hom.: 1036 Cov.: 31 AF XY: 0.0218 AC XY: 15883 AN XY: 726938

African (AFR) AF: 0.0151 AC: 506 AN: 33466

American (AMR) AF: 0.0177 AC: 793 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 547 AN: 26114

East Asian (EAS) AF: 0.172 AC: 6835 AN: 39672

South Asian (SAS) AF: 0.0679 AC: 5854 AN: 86248

European-Finnish (FIN) AF: 0.0225 AC: 1203 AN: 53394

Middle Eastern (MID) AF: 0.0303 AC: 175 AN: 5768

European-Non Finnish (NFE) AF: 0.0110 AC: 12172 AN: 1111518

Other (OTH) AF: 0.0246 AC: 1484 AN: 60374

GnomAD4 genome AF: 0.0212 AC: 3232 AN: 152310 Hom.: 101 Cov.: 32 AF XY: 0.0234 AC XY: 1745 AN XY: 74466

African (AFR) AF: 0.0156 AC: 647 AN: 41570

American (AMR) AF: 0.0170 AC: 260 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.154 AC: 795 AN: 5178

South Asian (SAS) AF: 0.0804 AC: 388 AN: 4828

European-Finnish (FIN) AF: 0.0219 AC: 233 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 765 AN: 68032

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0125 Hom.: 31

Bravo AF: 0.0200

Asia WGS AF: 0.114 AC: 395 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0121

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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	-0.53
CADD	Benign	7.5
DANN	Benign	0.64
PhyloP100		0.30
Mutation Taster		=98/2	polymorphism (auto)

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: rs2306220; hg19: chr6-129511373; COSMIC: COSV70340942;