Genetic Variant NEB:p.Ile8020Leu (chr2-151499354-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164507.2(NEB):c.24058A>C(p.Ile8020Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,394,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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. I8020V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

1 publications found

Variant links:

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB links:

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.13379493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.24058A>C	p.Ile8020Leu	missense_variant	Exon 169 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.24058A>C	p.Ile8020Leu	missense_variant	Exon 169 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.24058A>C	p.Ile8020Leu	missense_variant	Exon 169 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.24058A>C	p.Ile8020Leu	missense_variant	Exon 169 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000642

AC:

AN:

155698

AF XY:

0.0000121

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1394768

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

688146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31458

American (AMR)

AF:

0.00

AC:

AN:

35492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35494

South Asian (SAS)

AF:

0.00

AC:

AN:

79008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0000204

AC:

AN:

1075972

Other (OTH)

AF:

0.00

AC:

AN:

57842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0

.;T;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.042

T;T;T;.;.

M_CAP

Benign

0.0076

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

1.1

PROVEAN

Benign

-0.17

N;.;N;.;.

REVEL

Benign

0.016

Sift

Benign

0.95

T;.;T;.;.

Sift4G

Benign

0.12

T;T;T;T;T

Vest4

0.34

ClinPred

0.13

GERP RS

3.5

gMVP

0.021

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over