chr2-151549666-G-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_001164507.2(NEB):​c.20019C>T​(p.His6673His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,600,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.446

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 2-151549666-G-A is Benign according to our data. Variant chr2-151549666-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 465531.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.446 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEBNM_001164507.2 linkc.20019C>T p.His6673His synonymous_variant Exon 130 of 182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkc.20019C>T p.His6673His synonymous_variant Exon 130 of 182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkc.20019C>T p.His6673His synonymous_variant Exon 130 of 182 5 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkc.20019C>T p.His6673His synonymous_variant Exon 130 of 182 5 NM_001164507.2 ENSP00000416578.2 P20929-3

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
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:
0.0000218
AC:
5
AN:
229024
AF XY:
0.0000244
show subpopulations
Gnomad AFR exome
AF:
0.000284
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:
0.00000976
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000414
AC:
6
AN:
1448714
Hom.:
0
Cov.:
30
AF XY:
0.00000695
AC XY:
5
AN XY:
719012
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000900
AC:
3
AN:
33346
American (AMR)
AF:
0.00
AC:
0
AN:
43104
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25836
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39302
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83538
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52682
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5744
European-Non Finnish (NFE)
AF:
0.00000181
AC:
2
AN:
1105248
Other (OTH)
AF:
0.00
AC:
0
AN:
59914
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000047), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.383
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000591
AC:
9
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74362
show subpopulations
African (AFR)
AF:
0.000217
AC:
9
AN:
41438
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.431
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000986
Hom.:
0
Bravo
AF:
0.0000793

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Benign:1
Oct 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
CADD
Benign
8.3
DANN
Benign
0.35
PhyloP100
0.45
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs374881368; hg19: chr2-152406180; API