rs45628140

Variant names:

• chr10-20831592-A-C
• rs45628140
• NM_006393.3:c.1450-9T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006393.3(NEBL):​c.1450-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,550,754 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: NEBL NM_006393.3 intron
• Scores: Splicing: ADA: 0.7220
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.365
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 10-20831592-A-C is Benign according to our data. Variant chr10-20831592-A-C is described in ClinVar as Benign. ClinVar VariationId is 164752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 411 AD gene.

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.1450-9T>G		intron	N/A	NP_006384.1
	NEBL	NM_001377322.1		c.358-18652T>G		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-18652T>G		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.1450-9T>G		intron	N/A	ENSP00000366326.4
	NEBL	ENST00000417816.2	TSL:1	c.358-18652T>G		intron	N/A	ENSP00000393896.2
	NEBL	ENST00000493005.5	TSL:1	n.50-9T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 151866 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00139 AC: 347 AN: 249808 AF XY: 0.00117

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000584

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000794 AC: 1111 AN: 1398770 Hom.: 2 Cov.: 25 AF XY: 0.000799 AC XY: 559 AN XY: 699632

African (AFR) AF: 0.00876 AC: 281 AN: 32062

American (AMR) AF: 0.00263 AC: 117 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 117 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 84864

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52766

Middle Eastern (MID) AF: 0.00373 AC: 21 AN: 5630

European-Non Finnish (NFE) AF: 0.000425 AC: 449 AN: 1055454

Other (OTH) AF: 0.00214 AC: 125 AN: 58376

GnomAD4 genome AF: 0.00270 AC: 411 AN: 151984 Hom.: 4 Cov.: 31 AF XY: 0.00250 AC XY: 186 AN XY: 74280

African (AFR) AF: 0.00724 AC: 300 AN: 41436

American (AMR) AF: 0.00289 AC: 44 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67978

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00317

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	NEBL-related disorder (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		0.36
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.50
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: rs45628140; hg19: chr10-21120521;