rs12618063

Positions:

Variant summary

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

The NM_001164507.2(NEB):c.3879+20G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,502,142 control chromosomes in the GnomAD database, including 20,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3382 hom., cov: 32)

Exomes 𝑓: 0.13 ( 17442 hom. )

Consequence

NEB
NM_001164507.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.371

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:

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=-0.86).

BP6

Variant 2-151675267-C-A is Benign according to our data. Variant chr2-151675267-C-A is described in ClinVar as [Benign]. Clinvar id is 167337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151675267-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 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.3879+20G>T		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.3879+20G>T		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.3879+20G>T	intron_variant	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.3879+20G>T	intron_variant	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.3879+20G>T	intron_variant	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.180

AC:

27402

AN:

151932

Hom.:

3366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.489

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.170

GnomAD3 exomes

AF:

0.171

AC:

30628

AN:

179444

Hom.:

3790

AF XY:

0.176

AC XY:

16593

AN XY:

94432

show subpopulations

Gnomad AFR exome

AF:

0.308

Gnomad AMR exome

AF:

0.0861

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.467

Gnomad SAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.134

AC:

181307

AN:

1350092

Hom.:

17442

Cov.:

AF XY:

0.138

AC XY:

92516

AN XY:

670062

show subpopulations

Gnomad4 AFR exome

AF:

0.315

Gnomad4 AMR exome

AF:

0.0910

Gnomad4 ASJ exome

AF:

0.158

Gnomad4 EAS exome

AF:

0.507

Gnomad4 SAS exome

AF:

0.277

Gnomad4 FIN exome

AF:

0.117

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.162

GnomAD4 genome

AF:

0.181

AC:

27466

AN:

152050

Hom.:

3382

Cov.:

AF XY:

0.182

AC XY:

13539

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.302

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.156

Gnomad4 EAS

AF:

0.490

Gnomad4 SAS

AF:

0.282

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.179

Alfa

AF:

0.141

Hom.:

440

Bravo

AF:

0.184

Asia WGS

AF:

0.424

AC:

1471

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	Variant summary: The NEB c.3879+20G>T variant involves the alteration of a non-conserved intronic nucleotide and 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 35623/207000 control chromosomes (109 homozygotes) at a frequency of 0.1720918, which is approximately 49 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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	Eurofins Ntd Llc (ga)	Nov 26, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Arthrogryposis multiplex congenita 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.8

DANN

Benign

0.34

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.

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