dbSNP rs368856187: NEBL:p.Ala87Pro (chr10-20888207-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/24 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

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.259G>C	p.Ala87Pro	missense_variant, splice_region_variant	Exon 4 of 28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.259G>C	p.Ala87Pro	missense_variant, splice_region_variant	Exon 4 of 28	1	NM_006393.3	ENSP00000366326.4

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

GnomAD2 exomes

AF:

0.00000420

AC:

AN:

238274

AF XY:

0.00

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 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

African (AFR)

AF:

0.0000306

AC:

AN:

32686

American (AMR)

AF:

0.00

AC:

AN:

44338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

83908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087804

Other (OTH)

AF:

0.00

AC:

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000160

AC:

AN:

125298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60316

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000694

AC:

AN:

28828

American (AMR)

AF:

0.00

AC:

AN:

12024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3274

East Asian (EAS)

AF:

0.00

AC:

AN:

4850

South Asian (SAS)

AF:

0.00

AC:

AN:

4014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61470

Other (OTH)

AF:

0.00

AC:

AN:

1708

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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;.

PhyloP100

1.5

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;.

Vest4

0.52

ClinPred

0.15

GERP RS

2.9

Varity_R

0.40

gMVP

0.70

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over