dbSNP rs114918858: NEBL:p.Pro4Leu (chr10-20897195-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006393.3(NEBL):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,595,888 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 8 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.71

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054856837).

BP6

Variant 10-20897195-G-A is Benign according to our data. Variant chr10-20897195-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00459 (698/152066) while in subpopulation AFR AF = 0.016 (664/41454). AF 95% confidence interval is 0.015. There are 6 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 698 AD gene.

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
NEBL	NM_006393.3	MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 28	NP_006384.1
NEBL	NM_001377322.1		c.357+64477C>T		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.357+64477C>T		intron	N/A	NP_998734.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEBL	ENST00000377122.9	TSL:1 MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 28	ENSP00000366326.4
NEBL	ENST00000417816.2	TSL:1	c.357+64477C>T		intron	N/A	ENSP00000393896.2
NEBL	ENST00000863069.1		c.11C>T	p.Pro4Leu	missense	Exon 1 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes

AF:

0.00459

AC:

698

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00106

AC:

235

AN:

222620

AF XY:

0.000717

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.000533

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000105

Gnomad OTH exome

AF:

0.000535

GnomAD4 exome

AF:

0.000448

AC:

647

AN:

1443822

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

264

AN XY:

717380

show subpopulations

African (AFR)

AF:

0.0169

AC:

558

AN:

32998

American (AMR)

AF:

0.000698

AC:

AN:

42990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39336

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000545

AC:

AN:

1100102

Other (OTH)

AF:

0.000854

AC:

AN:

59694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00459

AC:

698

AN:

152066

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

341

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0160

AC:

664

AN:

41454

American (AMR)

AF:

0.00164

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00163

Hom.:

Bravo

AF:

0.00514

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00124

AC:

149

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

NEBL-related disorder (1)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

Eigen

Benign

-0.047

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

2.7

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.092

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0080

Vest4

0.15

MVP

0.56

MPC

0.016

ClinPred

0.065

GERP RS

5.8

PromoterAI

-0.00010

Neutral

(source)

Varity_R

0.34

gMVP

0.39

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over