rs113048349

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164508.2(NEB):c.24208-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,567,582 control chromosomes in the GnomAD database, including 141 homozygotes. 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 0.0089 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 134 hom. )

Consequence

NEB
NM_001164508.2 splice_region, intron

Scores

Splicing: ADA: 0.00003053

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.516

Publications

4 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 links:

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]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 2-151497725-G-A is Benign according to our data. Variant chr2-151497725-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00891 (1356/152222) while in subpopulation NFE AF = 0.0121 (820/68014). AF 95% confidence interval is 0.0114. There are 7 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.24208-7C>T		splice_region_variant, intron_variant	Intron 170 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.24208-7C>T		splice_region_variant, intron_variant	Intron 170 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.24208-7C>T		splice_region_variant, intron_variant	Intron 170 of 181	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.24208-7C>T		splice_region_variant, intron_variant	Intron 170 of 181	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00890

AC:

1354

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.0106

AC:

1899

AN:

179642

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00317

Gnomad ASJ exome

AF:

0.0432

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0118

AC:

16686

AN:

1415360

Hom.:

134

Cov.:

AF XY:

0.0118

AC XY:

8244

AN XY:

699410

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

32466

American (AMR)

AF:

0.00391

AC:

147

AN:

37602

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

1108

AN:

25500

East Asian (EAS)

AF:

0.0000263

AC:

AN:

37964

South Asian (SAS)

AF:

0.0108

AC:

867

AN:

80018

European-Finnish (FIN)

AF:

0.0112

AC:

567

AN:

50822

Middle Eastern (MID)

AF:

0.0126

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0120

AC:

13019

AN:

1086578

Other (OTH)

AF:

0.0145

AC:

852

AN:

58700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

893

1786

2678

3571

4464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00891

AC:

1356

AN:

152222

Hom.:

Cov.:

AF XY:

0.00891

AC XY:

663

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41534

American (AMR)

AF:

0.00654

AC:

100

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0386

AC:

134

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00892

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10590

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0121

AC:

820

AN:

68014

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

214

285

356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00933

Hom.:

Bravo

AF:

0.00812

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 31, 2017

GeneDx

Significance: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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

24313-7C>T in intron 171 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 1.3% (42/3182) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs113048349). -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 07, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BP4, BS1, BS2 -

Nemaline myopathy 2

Benign:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.41

(source)

DANN

Benign

0.58

PhyloP100

-0.52

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0020

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

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rs113048349

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over