rs923819811

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-20888220-A-C
• chr10-20888220-A-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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_006393.3	MANE Select	c.259-13T>G		intron	N/A	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.357+73452T>G		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.357+73452T>G		intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.259-13T>G		intron	N/A	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.357+73452T>G		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.259-13T>G		intron	N/A	ENSP00000533128.1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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;