dbSNP rs536400111: NEBL:p.Ile9Met (chr10-20897179-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006393.3(NEBL):c.27A>G(p.Ile9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. I9T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.441

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02996564).

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.27A>G	p.Ile9Met	missense	Exon 1 of 28	NP_006384.1
NEBL	NM_001377322.1		c.357+64493A>G		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.357+64493A>G		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.27A>G	p.Ile9Met	missense	Exon 1 of 28	ENSP00000366326.4
NEBL	ENST00000417816.2	TSL:1	c.357+64493A>G		intron	N/A	ENSP00000393896.2
NEBL	ENST00000377119.5	TSL:5	n.37A>G		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453230

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33300

American (AMR)

AF:

0.00

AC:

AN:

44226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

85726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105356

Other (OTH)

AF:

0.00

AC:

AN:

60126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.22

M_CAP

Benign

0.0061

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

-0.44

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.62

REVEL

Benign

0.061

Sift

Uncertain

0.022

Sift4G

Benign

0.095

Polyphen

0.0

Vest4

0.047

MutPred

0.15

Gain of catalytic residue at V5 (P = 0.0452)

MVP

0.35

MPC

0.017

ClinPred

0.043

GERP RS

-6.6

PromoterAI

0.0099

Neutral

(source)

Varity_R

0.11

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over