Variant 2-151697590-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):c.1211C>A(p.Thr404Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T404I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.86

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.1211C>A	p.Thr404Asn	missense_variant	14/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.1211C>A	p.Thr404Asn	missense_variant	14/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.1211C>A	p.Thr404Asn	missense_variant	14/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.1211C>A	p.Thr404Asn	missense_variant	14/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000489048.1 linkuse as main transcript	n.110C>A		non_coding_transcript_exon_variant	2/12	1
NEB	ENST00000409198.5 linkuse as main transcript	c.1211C>A	p.Thr404Asn	missense_variant	14/150	5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.73

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

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.8

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.1

N;N;.;N;N;.;.

REVEL

Benign

0.26

Sift

Uncertain

0.0050

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.97

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

Vest4

0.76

MutPred

0.48

Loss of catalytic residue at T404 (P = 0.0497);Loss of catalytic residue at T404 (P = 0.0497);Loss of catalytic residue at T404 (P = 0.0497);Loss of catalytic residue at T404 (P = 0.0497);Loss of catalytic residue at T404 (P = 0.0497);Loss of catalytic residue at T404 (P = 0.0497);Loss of catalytic residue at T404 (P = 0.0497);

MVP

0.56

MPC

0.36

ClinPred

0.99

GERP RS

6.0

Varity_R

0.43

gMVP

0.46

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over