NM_006393.3:c.259-13T>G

Variant names:

• chr10-20888220-A-C
• rs923819811
• NM_006393.3:c.259-13T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006393.3(NEBL):​c.259-13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,402,784 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: NEBL NM_006393.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

Genes affected

NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

NEBL Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-20888220-A-C is Benign according to our data. Variant chr10-20888220-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 506239.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3	c.259-13T>G		intron_variant	Intron 3 of 27	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9	c.259-13T>G		intron_variant	Intron 3 of 27	1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes AF: 0.0000732 AC: 7 AN: 95648 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 160850 AF XY: 0.00

Gnomad AFR exome AF: 0.0000887

Gnomad AMR exome AF: 0.0000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000995 AC: 13 AN: 1307136 Hom.: 0 Cov.: 20 AF XY: 0.00000759 AC XY: 5 AN XY: 658598

African (AFR) AF: 0.000166 AC: 5 AN: 30128

American (AMR) AF: 0.000114 AC: 5 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 38880

South Asian (SAS) AF: 0.00 AC: 0 AN: 81048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5406

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 974338

Other (OTH) AF: 0.0000544 AC: 3 AN: 55196

GnomAD4 genome AF: 0.0000732 AC: 7 AN: 95648 Hom.: 0 Cov.: 30 AF XY: 0.0000432 AC XY: 2 AN XY: 46246

African (AFR) AF: 0.000164 AC: 5 AN: 30452

American (AMR) AF: 0.000223 AC: 2 AN: 8968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2550

East Asian (EAS) AF: 0.00 AC: 0 AN: 4280

South Asian (SAS) AF: 0.00 AC: 0 AN: 3018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39598

Other (OTH) AF: 0.00 AC: 0 AN: 1328

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.259-13T>G var iant in NEBL has not been previously reported in individuals with cardiomyopathy . This variant has been identified in 2/17494 African chromosomes and 1/21470 La tin chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dnSNP rs 923819811). This variant is located in the 5' splice regi on. Computational tools do not suggest an impact to splicing. However, this info rmation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the c.259-13T>G variant is uncertain. ACMG/AMP Criteria ap plied: PM2; BP4. -

Primary dilated cardiomyopathy Benign:1

May 25, 2024

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	-0.85
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		1.2

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: rs923819811; hg19: chr10-21177149;