rs75118047

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.1675-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,567,594 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 80 hom. )

Consequence

NEB
NM_001164508.2 intron

Scores

Splicing: ADA: 0.006701

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0850

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:

NEB (HGNC:):

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-151694638-A-C is Benign according to our data. Variant chr2-151694638-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 129727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.1675-9T>G		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.1675-9T>G		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.1675-9T>G	intron_variant	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.1675-9T>G	intron_variant	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000489048.1 linkuse as main transcript	n.574-9T>G	intron_variant	1
NEB	ENST00000409198.5 linkuse as main transcript	c.1675-9T>G	intron_variant	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

582

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00793

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0579

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00791

AC:

1410

AN:

178324

Hom.:

AF XY:

0.00743

AC XY:

703

AN XY:

94584

show subpopulations

Gnomad AFR exome

AF:

0.000395

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0644

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.00715

Gnomad NFE exome

AF:

0.000476

Gnomad OTH exome

AF:

0.00519

GnomAD4 exome

AF:

0.00255

AC:

3610

AN:

1415296

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

1778

AN XY:

699704

show subpopulations

Gnomad4 AFR exome

AF:

0.000155

Gnomad4 AMR exome

AF:

0.0122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0550

Gnomad4 SAS exome

AF:

0.00186

Gnomad4 FIN exome

AF:

0.00799

Gnomad4 NFE exome

AF:

0.000241

Gnomad4 OTH exome

AF:

0.00463

GnomAD4 genome

AF:

0.00381

AC:

581

AN:

152298

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00792

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0575

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00800

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000950

Hom.:

Bravo

AF:

0.00413

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -

Nemaline myopathy 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0067

dbscSNV1_RF

Benign

0.31

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over