rs117096733

Variant names:

• chr6-129297646-T-C
• rs117096733
• NM_000426.4:c.2857-39T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-129297646-T-C
• chr6-129297646-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 256062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129297646-T-C is described in Lovd as [Benign]. Variant chr6-129297646-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,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

GnomAD3 exomes AF: 0.0108 AC: 2704 AN: 249598 Hom.: 20 AF XY: 0.0110 AC XY: 1487 AN XY: 134974

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 SAS exome AF: 0.00910

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

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.00829

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00947

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0136

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

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00572 Hom.: 0

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

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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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
BranchPoint Hunter		3.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs117096733; hg19: chr6-129618791;