chr2-151526203-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001164507.2(NEB):​c.22005G>A​(p.Thr7335Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,613,886 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T7335T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00080 ( 8 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.742

Publications

1 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]
RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 2-151526203-C-T is Benign according to our data. Variant chr2-151526203-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194142.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BP7
Synonymous conserved (PhyloP=-0.742 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000854 (130/152280) while in subpopulation SAS AF = 0.00477 (23/4818). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEBNM_001164507.2 linkc.22005G>A p.Thr7335Thr synonymous_variant Exon 149 of 182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkc.22005G>A p.Thr7335Thr synonymous_variant Exon 149 of 182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkc.22005G>A p.Thr7335Thr synonymous_variant Exon 149 of 182 5 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkc.22005G>A p.Thr7335Thr synonymous_variant Exon 149 of 182 5 NM_001164507.2 ENSP00000416578.2 P20929-3

Frequencies

GnomAD3 genomes
AF:
0.000861
AC:
131
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00203
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00477
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000867
Gnomad OTH
AF:
0.00143
GnomAD2 exomes
AF:
0.00109
AC:
272
AN:
248808
AF XY:
0.00132
show subpopulations
Gnomad AFR exome
AF:
0.000194
Gnomad AMR exome
AF:
0.000406
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000929
Gnomad NFE exome
AF:
0.000976
Gnomad OTH exome
AF:
0.00149
GnomAD4 exome
AF:
0.000802
AC:
1172
AN:
1461606
Hom.:
8
Cov.:
32
AF XY:
0.000927
AC XY:
674
AN XY:
727076
show subpopulations
African (AFR)
AF:
0.0000896
AC:
3
AN:
33478
American (AMR)
AF:
0.000492
AC:
22
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.000918
AC:
24
AN:
26134
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39672
South Asian (SAS)
AF:
0.00414
AC:
357
AN:
86252
European-Finnish (FIN)
AF:
0.0000562
AC:
3
AN:
53396
Middle Eastern (MID)
AF:
0.00121
AC:
7
AN:
5768
European-Non Finnish (NFE)
AF:
0.000639
AC:
710
AN:
1111818
Other (OTH)
AF:
0.000729
AC:
44
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
67
134
202
269
336
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.000854
AC:
130
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.000779
AC XY:
58
AN XY:
74458
show subpopulations
African (AFR)
AF:
0.000217
AC:
9
AN:
41566
American (AMR)
AF:
0.00203
AC:
31
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00115
AC:
4
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00477
AC:
23
AN:
4818
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.000868
AC:
59
AN:
68006
Other (OTH)
AF:
0.00142
AC:
3
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
6
13
19
26
32
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:
0.000763
Hom.:
0
Bravo
AF:
0.000854
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1Benign:2
Nov 11, 2019
Natera, Inc.
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:3
Nov 21, 2017
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 19, 2015
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Nov 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

NEB: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
0.60
DANN
Benign
0.55
PhyloP100
-0.74
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs201400523; hg19: chr2-152382717; COSMIC: COSV104384787; COSMIC: COSV104384787; API