Variant rs368856187 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006393.3(NEBL):c.259G>C(p.Ala87Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,557,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A87T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Splicing: ADA: 0.2421

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17563355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.259G>C	p.Ala87Pro	missense_variant, splice_region_variant	4/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.259G>C	p.Ala87Pro	missense_variant, splice_region_variant	4/28	1	NM_006393.3		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0000160

AC:

AN:

125298

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000694

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000420

AC:

AN:

238274

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128672

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

6.98e-7

AC:

AN:

1432562

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000160

AC:

AN:

125298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60316

show subpopulations

Gnomad4 AFR

AF:

0.0000694

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.0062

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.87

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.16

Sift

Benign

0.15

T;T

Sift4G

Benign

0.18

T;.

Polyphen

0.28

B;.

Vest4

0.52

MutPred

0.52

Gain of glycosylation at A87 (P = 0.0468);.;

MVP

0.45

MPC

0.030

ClinPred

0.15

GERP RS

2.9

Varity_R

0.40

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over