chr6-129297646-T-C

Variant names:

• chr6-129297646-T-C
• rs117096733
• NM_000426.4:c.2857-39T>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.2857-39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,598,178 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 33)
  • Exomes 𝑓: 0.015 (194 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.667
• Publications: 1 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-129297646-T-C is Benign according to our data. Variant chr6-129297646-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 256062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1565/152310) while in subpopulation NFE AF = 0.0163 (1112/68014). AF 95% confidence interval is 0.0156. There are 11 homozygotes in GnomAd4. There are 727 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2857-39T>C		intron_variant	Intron 20 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2857-39T>C		intron_variant	Intron 20 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2857-39T>C		intron_variant	Intron 20 of 64	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.3121-39T>C		intron_variant	Intron 21 of 65	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.2857-39T>C		intron_variant	Intron 20 of 63	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1562 AN: 152192 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.0108 AC: 2704 AN: 249598 AF XY: 0.0110

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.00886

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0146 AC: 21128 AN: 1445868 Hom.: 194 Cov.: 29 AF XY: 0.0146 AC XY: 10517 AN XY: 720248

African (AFR) AF: 0.00248 AC: 82 AN: 33124

American (AMR) AF: 0.00557 AC: 248 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00829 AC: 216 AN: 26040

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39622

South Asian (SAS) AF: 0.0101 AC: 869 AN: 85792

European-Finnish (FIN) AF: 0.00947 AC: 505 AN: 53302

Middle Eastern (MID) AF: 0.0102 AC: 44 AN: 4326

European-Non Finnish (NFE) AF: 0.0167 AC: 18349 AN: 1099380

Other (OTH) AF: 0.0136 AC: 812 AN: 59740

GnomAD4 genome AF: 0.0103 AC: 1565 AN: 152310 Hom.: 11 Cov.: 33 AF XY: 0.00976 AC XY: 727 AN XY: 74484

African (AFR) AF: 0.00358 AC: 149 AN: 41576

American (AMR) AF: 0.00817 AC: 125 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4830

European-Finnish (FIN) AF: 0.00781 AC: 83 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0163 AC: 1112 AN: 68014

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0139 Hom.: 24

Bravo AF: 0.00938

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 11, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.83
CADD	Benign	5.9
DANN	Benign	0.65
PhyloP100		0.67
BranchPoint Hunter		3.0
Mutation Taster		=100/0	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: rs117096733; hg19: chr6-129618791;