NM_006393.3:c.496G>C

Variant names:

• chr10-20869826-C-G
• rs780036701
• NM_006393.3:c.496G>C

Variant summary

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

The NM_006393.3(NEBL):​c.496G>C​(p.Asp166His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D166E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NEBL NM_006393.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15
• 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

LOC102725112 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.496G>C	p.Asp166His	missense	Exon 6 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-56886G>C		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-56886G>C		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.496G>C	p.Asp166His	missense	Exon 6 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-56886G>C		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.496G>C	p.Asp166His	missense	Exon 6 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.14
Sift	Benign	0.049	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.63
MutPred		0.32		Gain of MoRF binding (P = 0.0364)
MVP		0.61
MPC		0.091
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.29
gMVP		0.65
Mutation Taster		=83/17	polymorphism

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: rs780036701; hg19: chr10-21158755;