chr2-151610873-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_001164507.2(NEB):​c.11806-7C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,560,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NEB
NM_001164507.2 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.002263
2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: -0.0150
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BP6
Variant 2-151610873-G-T is Benign according to our data. Variant chr2-151610873-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 257724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBNM_001164507.2 linkuse as main transcriptc.11806-7C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkuse as main transcriptc.11806-7C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.11806-7C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 NM_001164508.2 ENSP00000380505 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.11806-7C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 NM_001164507.2 ENSP00000416578 A2P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.11077-7C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 ENSP00000386259 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000211
AC:
4
AN:
189850
Hom.:
0
AF XY:
0.0000198
AC XY:
2
AN XY:
100968
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000488
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000248
AC:
35
AN:
1408778
Hom.:
0
Cov.:
29
AF XY:
0.0000287
AC XY:
20
AN XY:
696490
show subpopulations
Gnomad4 AFR exome
AF:
0.0000309
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000405
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000251
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000213
Gnomad4 OTH exome
AF:
0.000120
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000126
Hom.:
0
Bravo
AF:
0.0000340
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1Benign:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 24, 2020- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.76
CADD
Benign
6.4
DANN
Benign
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0023
dbscSNV1_RF
Benign
0.18
SpliceAI score (max)
0.040
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: rs779713133; hg19: chr2-152467387; API