dbSNP rs397517205: NEBL:p.Ala726Thr (chr10-20815690-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006393.3(NEBL):c.2176G>A(p.Ala726Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. A726D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34

Publications

2 publications found

Variant links:

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

NEBL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37561423).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEBL	NM_006393.3	MANE Select	c.2176G>A	p.Ala726Thr	missense	Exon 22 of 28	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-2750G>A		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-2750G>A		intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEBL	ENST00000377122.9	TSL:1 MANE Select	c.2176G>A	p.Ala726Thr	missense	Exon 22 of 28	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-2750G>A		intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000493005.5	TSL:1	n.1496G>A		non_coding_transcript_exon	Exon 9 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.78

M_CAP

Benign

0.033

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

7.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.18

Sift

Uncertain

0.018

Sift4G

Benign

0.18

Polyphen

0.27

Vest4

0.60

MutPred

0.54

Gain of disorder (P = 0.0665)

MVP

0.39

MPC

0.11

ClinPred

0.98

GERP RS

5.9

Varity_R

0.22

gMVP

0.23

Mutation Taster

=76/24

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over