10-20888214-GAAA-GA

Variant names:

• chr10-20888214-GAA-G
• rs57918610
• NM_006393.3:c.259-9_259-8delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006393.3(NEBL):​c.259-9_259-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,291,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: NEBL NM_006393.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.367
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3	c.259-9_259-8delTT		splice_region_variant, 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.259-9_259-8delTT		splice_region_variant, intron_variant	Intron 3 of 27	1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1291122 Hom.: 0 AF XY: 0.00000155 AC XY: 1 AN XY: 646936

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

African (AFR) AF: 0.00 AC: 0 AN: 29110

American (AMR) AF: 0.00 AC: 0 AN: 41056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23972

East Asian (EAS) AF: 0.00 AC: 0 AN: 37128

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 972380

Other (OTH) AF: 0.00 AC: 0 AN: 53588

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.37

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: rs57918610; hg19: chr10-21177143;