rs1365594299

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001164507.2(NEB):c.12596C>T(p.Pro4199Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4199P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000012 ( 0 hom., cov: 11)

Exomes 𝑓: 0.000013 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.40

Publications

0 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 Gene-Disease associations (from GenCC):

nemaline myopathy 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12596C>T	p.Pro4199Leu	missense_variant	Exon 83 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12596C>T	p.Pro4199Leu	missense_variant	Exon 83 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.12596C>T	p.Pro4199Leu	missense_variant	Exon 83 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.12596C>T	p.Pro4199Leu	missense_variant	Exon 83 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+2262C>T		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0000123

AC:

AN:

81406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000298

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:

0.0000477

AC:

AN:

83828

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000273

Gnomad AMR exome

AF:

0.000200

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000128

AC:

AN:

623588

Hom.:

Cov.:

AF XY:

0.00000624

AC XY:

AN XY:

320434

show subpopulations

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

African (AFR)

AF:

0.0000727

AC:

AN:

27494

American (AMR)

AF:

0.000116

AC:

AN:

17174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17814

East Asian (EAS)

AF:

0.00

AC:

AN:

19506

South Asian (SAS)

AF:

0.00

AC:

AN:

58278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2288

European-Non Finnish (NFE)

AF:

0.00000928

AC:

AN:

430820

Other (OTH)

AF:

0.00

AC:

AN:

29930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000123

AC:

AN:

81406

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

38372

show subpopulations

African (AFR)

AF:

0.0000298

AC:

AN:

33570

American (AMR)

AF:

0.00

AC:

AN:

5212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2218

East Asian (EAS)

AF:

0.00

AC:

AN:

2174

South Asian (SAS)

AF:

0.00

AC:

AN:

2370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

30392

Other (OTH)

AF:

0.00

AC:

AN:

1002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2

Dec 20, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.051

.;T;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D;D;.;.

M_CAP

Benign

0.058

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Uncertain

0.39

PhyloP100

4.4

PROVEAN

Benign

-1.6

N;.;N;.;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.020

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.55

MutPred

0.83

Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);

MVP

0.79

MPC

0.33

ClinPred

0.091

GERP RS

3.7

gMVP

0.0068

Mutation Taster

=76/24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over