rs114959904

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001164508.2(NEB):​c.2640C>T​(p.Arg880Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000793 in 1,596,906 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

NEB
NM_001164508.2 splice_region, synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0890
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
Variant 2-151684973-G-A is Benign according to our data. Variant chr2-151684973-G-A is described in ClinVar as [Benign]. Clinvar id is 129737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.089 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00402 (612/152230) while in subpopulation AFR AF= 0.014 (583/41530). AF 95% confidence interval is 0.0131. There are 4 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBNM_001164507.2 linkuse as main transcriptc.2640C>T p.Arg880Arg splice_region_variant, synonymous_variant 28/182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkuse as main transcriptc.2640C>T p.Arg880Arg splice_region_variant, synonymous_variant 28/182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.2640C>T p.Arg880Arg splice_region_variant, synonymous_variant 28/1825 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.2640C>T p.Arg880Arg splice_region_variant, synonymous_variant 28/1825 NM_001164507.2 ENSP00000416578.2 P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.2640C>T p.Arg880Arg splice_region_variant, synonymous_variant 28/1505 ENSP00000386259.1 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.00403
AC:
613
AN:
152112
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0141
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000927
AC:
207
AN:
223304
Hom.:
2
AF XY:
0.000833
AC XY:
100
AN XY:
120096
show subpopulations
Gnomad AFR exome
AF:
0.0127
Gnomad AMR exome
AF:
0.000414
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000733
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000161
Gnomad OTH exome
AF:
0.000180
GnomAD4 exome
AF:
0.000453
AC:
654
AN:
1444676
Hom.:
3
Cov.:
30
AF XY:
0.000367
AC XY:
263
AN XY:
717024
show subpopulations
Gnomad4 AFR exome
AF:
0.0133
Gnomad4 AMR exome
AF:
0.000424
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000254
Gnomad4 SAS exome
AF:
0.0000599
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000105
Gnomad4 OTH exome
AF:
0.000935
GnomAD4 genome
AF:
0.00402
AC:
612
AN:
152230
Hom.:
4
Cov.:
32
AF XY:
0.00386
AC XY:
287
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0140
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00157
Hom.:
0
Bravo
AF:
0.00445
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxAug 22, 2018- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 11, 2018- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024NEB: BP4, BP7, BS1, BS2 -
Nemaline myopathy 2 Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 05, 2019- -
not specified Benign:1
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.37
CADD
Benign
4.9
DANN
Benign
0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs114959904; hg19: chr2-152541487; COSMIC: COSV99425625; COSMIC: COSV99425625; API