dbSNP rs747783456: LAMA2:c.7301-9C>A (chr6-129473205-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000426.4(LAMA2):c.7301-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 intron

Scores

Splicing: ADA: 0.001634

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.988

Publications

0 publications found

Variant links:

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)

LAMA2 links:

ENSG00000226149 (HGNC:):

ENSG00000226149 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 6-129473205-C-A is Benign according to our data. Variant chr6-129473205-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 645604.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.7301-9C>A		intron_variant	Intron 51 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.7301-9C>A		intron_variant	Intron 51 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 link	c.7301-9C>A	intron_variant	Intron 51 of 64	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 link	c.7565-9C>A	intron_variant	Intron 52 of 65	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 link	c.7301-9C>A	intron_variant	Intron 51 of 63	5		ENSP00000481744.2	A0A087WYF1
ENSG00000226149	ENST00000665046.1 link	n.975+29400G>T	intron_variant	Intron 9 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1425988

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711738

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32738

American (AMR)

AF:

0.00

AC:

AN:

44534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

39286

South Asian (SAS)

AF:

0.00

AC:

AN:

85376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1080556

Other (OTH)

AF:

0.0000169

AC:

AN:

59122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

LAMA2-related muscular dystrophy

Benign:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.53

PhyloP100

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over