10-20888214-GAAA-GAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_006393.3(NEBL):​c.259-9_259-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 1,290,878 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEBL NM_006393.3 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 10-20888214-G-GAA is Benign according to our data. Variant chr10-20888214-G-GAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3048372.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_006393.3	MANE Select	c.259-9_259-8dupTT		splice_region intron	N/A	NP_006384.1
	NEBL	NM_001377322.1		c.357+73456_357+73457dupTT		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.357+73456_357+73457dupTT		intron	N/A	NP_998734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.259-8_259-7insTT		splice_region intron	N/A	ENSP00000366326.4
	NEBL	ENST00000417816.2	TSL:1	c.357+73457_357+73458insTT		intron	N/A	ENSP00000393896.2
	NEBL	ENST00000377119.5	TSL:5	n.269-8_269-7insTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 113350 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000328 AC: 7 AN: 213600 AF XY: 0.0000259

Gnomad AFR exome AF: 0.000420

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000640

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 39 AN: 1290878 Hom.: 0 Cov.: 23 AF XY: 0.0000309 AC XY: 20 AN XY: 646814

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

African (AFR) AF: 0.000897 AC: 26 AN: 28998

American (AMR) AF: 0.00 AC: 0 AN: 41052

Ashkenazi Jewish (ASJ) AF: 0.0000417 AC: 1 AN: 23970

East Asian (EAS) AF: 0.00 AC: 0 AN: 37122

South Asian (SAS) AF: 0.00 AC: 0 AN: 78230

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

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5248

European-Non Finnish (NFE) AF: 0.00000926 AC: 9 AN: 972270

Other (OTH) AF: 0.0000373 AC: 2 AN: 53580

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 113350 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 54536

African (AFR) AF: 0.00 AC: 0 AN: 34122

American (AMR) AF: 0.00 AC: 0 AN: 10272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2902

East Asian (EAS) AF: 0.00 AC: 0 AN: 4514

South Asian (SAS) AF: 0.00 AC: 0 AN: 3400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50038

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.00 Hom.: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NEBL-related disorder Benign:1

Dec 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.37

Splicing

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

Other links and lift over

dbSNP: rs57918610; hg19: chr10-21177143;