rs2296614

Variant names:

• chr10-20785795-T-C
• rs2296614
• NM_006393.3:c.2997A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006393.3(NEBL):​c.2997A>G​(p.Thr999Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,613,892 control chromosomes in the GnomAD database, including 5,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (635 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4674 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.181
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 10-20785795-T-C is Benign according to our data. Variant chr10-20785795-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.181 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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.2997A>G	p.Thr999Thr	synonymous	Exon 28 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.858A>G	p.Thr286Thr	synonymous	Exon 8 of 8	NP_001364251.1
	NEBL	NM_213569.2		c.765A>G	p.Thr255Thr	synonymous	Exon 7 of 7	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.2997A>G	p.Thr999Thr	synonymous	Exon 28 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.765A>G	p.Thr255Thr	synonymous	Exon 7 of 7	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.3006A>G	p.Thr1002Thr	synonymous	Exon 28 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13018 AN: 152124 Hom.: 634 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0543

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0800 AC: 20073 AN: 250986 AF XY: 0.0756

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0756 AC: 110490 AN: 1461650 Hom.: 4674 Cov.: 31 AF XY: 0.0746 AC XY: 54248 AN XY: 727130

African (AFR) AF: 0.120 AC: 3999 AN: 33462

American (AMR) AF: 0.148 AC: 6608 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 2509 AN: 26130

East Asian (EAS) AF: 0.00176 AC: 70 AN: 39682

South Asian (SAS) AF: 0.0587 AC: 5063 AN: 86258

European-Finnish (FIN) AF: 0.0539 AC: 2880 AN: 53410

Middle Eastern (MID) AF: 0.0830 AC: 478 AN: 5762

European-Non Finnish (NFE) AF: 0.0756 AC: 84093 AN: 1111858

Other (OTH) AF: 0.0793 AC: 4790 AN: 60380

GnomAD4 genome AF: 0.0855 AC: 13017 AN: 152242 Hom.: 635 Cov.: 32 AF XY: 0.0845 AC XY: 6286 AN XY: 74428

African (AFR) AF: 0.119 AC: 4921 AN: 41518

American (AMR) AF: 0.109 AC: 1664 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 320 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.0541 AC: 261 AN: 4820

European-Finnish (FIN) AF: 0.0524 AC: 557 AN: 10624

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0746 AC: 5072 AN: 68010

Other (OTH) AF: 0.0710 AC: 150 AN: 2114

Alfa AF: 0.0894 Hom.: 693

Bravo AF: 0.0923

Asia WGS AF: 0.0330 AC: 116 AN: 3478

EpiCase AF: 0.0761

EpiControl AF: 0.0759

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs2296614; hg19: chr10-21074724;