6-129464246-T-C

Variant names:

• chr6-129464246-T-C
• rs1414736
• NM_000426.4:c.6993-44T>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.6993-44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,545,330 control chromosomes in the GnomAD database, including 279,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32749 hom., cov: 31)
  • Exomes 𝑓: 0.59 (246378 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72
• Publications: 9 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=-0.9).
• BP6: Variant 6-129464246-T-C is Benign according to our data. Variant chr6-129464246-T-C is described in ClinVar as Benign. ClinVar VariationId is 256084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 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.6993-44T>C		intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.6993-44T>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.6993-44T>C		intron	N/A	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.7257-44T>C		intron	N/A	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.6993-44T>C		intron	N/A	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98143 AN: 151622 Hom.: 32701 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.629

GnomAD2 exomes AF: 0.610 AC: 152214 AN: 249648 AF XY: 0.605

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.648

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.553

Gnomad FIN exome AF: 0.562

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.594

GnomAD4 exome AF: 0.592 AC: 825441 AN: 1393590 Hom.: 246378 Cov.: 23 AF XY: 0.592 AC XY: 412991 AN XY: 697274

African (AFR) AF: 0.831 AC: 26611 AN: 32038

American (AMR) AF: 0.650 AC: 28897 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 15993 AN: 25582

East Asian (EAS) AF: 0.537 AC: 21095 AN: 39268

South Asian (SAS) AF: 0.636 AC: 54011 AN: 84888

European-Finnish (FIN) AF: 0.568 AC: 30216 AN: 53182

Middle Eastern (MID) AF: 0.599 AC: 3233 AN: 5400

European-Non Finnish (NFE) AF: 0.581 AC: 610675 AN: 1050740

Other (OTH) AF: 0.598 AC: 34710 AN: 58036

GnomAD4 genome AF: 0.648 AC: 98257 AN: 151740 Hom.: 32749 Cov.: 31 AF XY: 0.645 AC XY: 47861 AN XY: 74152

African (AFR) AF: 0.815 AC: 33781 AN: 41440

American (AMR) AF: 0.624 AC: 9477 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2131 AN: 3466

East Asian (EAS) AF: 0.541 AC: 2772 AN: 5122

South Asian (SAS) AF: 0.623 AC: 3001 AN: 4814

European-Finnish (FIN) AF: 0.549 AC: 5797 AN: 10556

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39181 AN: 67848

Other (OTH) AF: 0.625 AC: 1311 AN: 2096

Alfa AF: 0.608 Hom.: 70809

Bravo AF: 0.661

Asia WGS AF: 0.573 AC: 1992 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.44
PhyloP100		-1.7
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: rs1414736; hg19: chr6-129785391;