chr2-151607546-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP7BS2_Supporting

The NM_001164507.2(NEB):c.12597G>A(p.Pro4199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign 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 0.00026 ( 0 hom., cov: 11)

Exomes 𝑓: 0.000063 ( 6 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -1.44

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP7

Synonymous conserved (PhyloP=-1.44 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	NM_001164507.2	MANE Plus Clinical	c.12597G>A	p.Pro4199Pro	synonymous	Exon 83 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.12597G>A	p.Pro4199Pro	synonymous	Exon 83 of 182	NP_001157980.2
NEB	NM_001271208.2		c.12597G>A	p.Pro4199Pro	synonymous	Exon 83 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.12597G>A	p.Pro4199Pro	synonymous	Exon 83 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12597G>A	p.Pro4199Pro	synonymous	Exon 83 of 182	ENSP00000416578.2
NEB	ENST00000409198.5	TSL:5	c.11601+2263G>A		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

82006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000504

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000381

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:

0.0000326

Gnomad OTH

AF:

0.00101

GnomAD2 exomes

AF:

0.000107

AC:

AN:

83810

AF XY:

0.0000660

show subpopulations

Gnomad AFR exome

AF:

0.000682

Gnomad AMR exome

AF:

0.000400

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

AF:

0.0000630

AC:

AN:

619498

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

318560

show subpopulations

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

African (AFR)

AF:

0.000511

AC:

AN:

27388

American (AMR)

AF:

0.000350

AC:

AN:

17158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17798

East Asian (EAS)

AF:

0.00

AC:

AN:

19478

South Asian (SAS)

AF:

0.0000172

AC:

AN:

58198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2268

European-Non Finnish (NFE)

AF:

0.0000328

AC:

AN:

427180

Other (OTH)

AF:

0.000134

AC:

AN:

29748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000113945), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000256

AC:

AN:

82006

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

38674

show subpopulations

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

African (AFR)

AF:

0.000504

AC:

AN:

33748

American (AMR)

AF:

0.000381

AC:

AN:

5252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2228

East Asian (EAS)

AF:

0.00

AC:

AN:

2172

South Asian (SAS)

AF:

0.00

AC:

AN:

2392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.0000326

AC:

AN:

30656

Other (OTH)

AF:

0.00101

AC:

AN:

990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000149058), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.335

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:

0.000253

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.5

(source)

DANN

Benign

0.24

PhyloP100

-1.4

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over