6-129454325-T-C

Variant names:

• chr6-129454325-T-C
• rs2297742
• NM_000426.4:c.6707+37T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000426.4(LAMA2):​c.6707+37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,558,298 control chromosomes in the GnomAD database, including 15,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1656 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13707 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.08
• Publications: 3 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 6-129454325-T-C is Benign according to our data. Variant chr6-129454325-T-C is described in ClinVar as Benign. ClinVar VariationId is 256083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.6707+37T>C		intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.6707+37T>C		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.6707+37T>C		intron	N/A	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.6971+37T>C		intron	N/A	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.6707+37T>C		intron	N/A	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21723 AN: 152014 Hom.: 1658 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.157 AC: 36107 AN: 229938 AF XY: 0.153

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.0989

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.136 AC: 191826 AN: 1406166 Hom.: 13707 Cov.: 23 AF XY: 0.137 AC XY: 95924 AN XY: 701884

African (AFR) AF: 0.127 AC: 4059 AN: 31872

American (AMR) AF: 0.212 AC: 9208 AN: 43344

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 2423 AN: 25544

East Asian (EAS) AF: 0.203 AC: 7808 AN: 38530

South Asian (SAS) AF: 0.153 AC: 12805 AN: 83828

European-Finnish (FIN) AF: 0.159 AC: 8360 AN: 52494

Middle Eastern (MID) AF: 0.150 AC: 849 AN: 5658

European-Non Finnish (NFE) AF: 0.129 AC: 137924 AN: 1066598

Other (OTH) AF: 0.144 AC: 8390 AN: 58298

GnomAD4 genome AF: 0.143 AC: 21727 AN: 152132 Hom.: 1656 Cov.: 32 AF XY: 0.144 AC XY: 10729 AN XY: 74366

African (AFR) AF: 0.131 AC: 5422 AN: 41498

American (AMR) AF: 0.185 AC: 2828 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1090 AN: 5156

South Asian (SAS) AF: 0.161 AC: 774 AN: 4820

European-Finnish (FIN) AF: 0.149 AC: 1579 AN: 10590

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9111 AN: 68006

Other (OTH) AF: 0.147 AC: 311 AN: 2112

Alfa AF: 0.130 Hom.: 249

Bravo AF: 0.145

Asia WGS AF: 0.163 AC: 568 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		-2.1
Mutation Taster		=100/0	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: rs2297742; hg19: chr6-129775470; COSMIC: COSV70351263;