chr6-129427795-G-C

Variant names:

• chr6-129427795-G-C
• rs148451013
• NM_000426.4:c.5909G>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.5909G>C​(p.Cys1970Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000532 in 1,613,834 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.87
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005335897).
• BP6: Variant 6-129427795-G-C is Benign according to our data. Variant chr6-129427795-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235524.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 = 0.00283 (431/152288) while in subpopulation AFR AF = 0.00982 (408/41548). AF 95% confidence interval is 0.00903. There are 2 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.5909G>C	p.Cys1970Ser	missense	Exon 41 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.5909G>C	p.Cys1970Ser	missense	Exon 41 of 64	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.5909G>C	p.Cys1970Ser	missense	Exon 41 of 65	ENSP00000400365.2	P24043
	LAMA2	ENST00000618192.5	TSL:5	c.6173G>C	p.Cys2058Ser	missense	Exon 42 of 66	ENSP00000480802.2	A0A087WX80
	LAMA2	ENST00000617695.5	TSL:5	c.5909G>C	p.Cys1970Ser	missense	Exon 41 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00985

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.00239

GnomAD2 exomes AF: 0.000784 AC: 197 AN: 251268 AF XY: 0.000493

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1461546 Hom.: 3 Cov.: 30 AF XY: 0.000250 AC XY: 182 AN XY: 727104

African (AFR) AF: 0.0106 AC: 354 AN: 33456

American (AMR) AF: 0.000693 AC: 31 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111838

Other (OTH) AF: 0.000596 AC: 36 AN: 60378

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74478

African (AFR) AF: 0.00982 AC: 408 AN: 41548

American (AMR) AF: 0.00105 AC: 16 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000463 Hom.: 0

Bravo AF: 0.00355

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	LAMA2-related disorder (1)
-	-	1	LAMA2-related muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.082	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.2	N
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.47		Gain of disorder (P = 0.0286)
MVP		0.31
MPC		0.11
ClinPred		0.010	T
GERP RS		5.9
Varity_R		0.098
gMVP		0.18
Mutation Taster		=98/2	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: rs148451013; hg19: chr6-129748940;