chr2-151663816-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001164507.2(NEB):c.5495T>A(p.Ile1832Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I1832T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.5495T>A	p.Ile1832Asn	missense_variant	Exon 45 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.5495T>A	p.Ile1832Asn	missense_variant	Exon 45 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.5495T>A	p.Ile1832Asn	missense_variant	Exon 45 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.5495T>A	p.Ile1832Asn	missense_variant	Exon 45 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.5495T>A	p.Ile1832Asn	missense_variant	Exon 45 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

0.0061

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

.;.;T;.;T;.;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;.;.

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

M;M;.;M;M;M;M

PhyloP100

9.3

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.1

D;D;.;D;D;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;.;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;.;.

Vest4

0.89

MutPred

0.45

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);

MVP

0.54

MPC

0.44

ClinPred

0.99

GERP RS

5.5

Varity_R

0.72

gMVP

0.59

Mutation Taster

=64/36

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over