2-151656478-A-T

Position:

chr2-151656478-A-T

Variant summary

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

The NM_001164507.2(NEB):c.6184-14T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,568,950 control chromosomes in the GnomAD database, including 4,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1373 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2882 hom. )

Consequence

NEB
NM_001164507.2 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0720

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=-0.81).

BP6

Variant 2-151656478-A-T is Benign according to our data. Variant chr2-151656478-A-T is described in ClinVar as [Benign]. Clinvar id is 226846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 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.6184-14T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.6184-14T>A		splice_polypyrimidine_tract_variant, 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.6184-14T>A	splice_polypyrimidine_tract_variant, intron_variant	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.6184-14T>A	splice_polypyrimidine_tract_variant, intron_variant	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.6184-14T>A	splice_polypyrimidine_tract_variant, intron_variant	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15447

AN:

152022

Hom.:

1370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0602

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0499

Gnomad SAS

AF:

0.0550

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0532

Gnomad OTH

AF:

0.0903

GnomAD3 exomes

AF:

0.0598

AC:

14166

AN:

236936

Hom.:

735

AF XY:

0.0576

AC XY:

7380

AN XY:

128222

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.0331

Gnomad ASJ exome

AF:

0.0909

Gnomad EAS exome

AF:

0.0448

Gnomad SAS exome

AF:

0.0562

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0522

Gnomad OTH exome

AF:

0.0565

GnomAD4 exome

AF:

0.0558

AC:

79013

AN:

1416810

Hom.:

2882

Cov.:

AF XY:

0.0552

AC XY:

38661

AN XY:

700956

show subpopulations

Gnomad4 AFR exome

AF:

0.231

Gnomad4 AMR exome

AF:

0.0361

Gnomad4 ASJ exome

AF:

0.0927

Gnomad4 EAS exome

AF:

0.0518

Gnomad4 SAS exome

AF:

0.0528

Gnomad4 FIN exome

AF:

0.0158

Gnomad4 NFE exome

AF:

0.0521

Gnomad4 OTH exome

AF:

0.0663

GnomAD4 genome

AF:

0.102

AC:

15470

AN:

152140

Hom.:

1373

Cov.:

AF XY:

0.0977

AC XY:

7264

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.0600

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.0496

Gnomad4 SAS

AF:

0.0545

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0533

Gnomad4 OTH

AF:

0.0894

Alfa

AF:

0.0397

Hom.:

Bravo

AF:

0.111

Asia WGS

AF:

0.0840

AC:

294

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	6184-14T>A in intron 48 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 22.5% (811/3602) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs10173335). -

Nemaline myopathy 2

Benign:3

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	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: c.6184-14T>A in NEB gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect the normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.06562 (7599 / 115796 chrs tested), including numerous homozygotes across multiple ethnicities. The observed frequency exceed the maximum expected allele frequency for a pathogenic variant of 0.0035. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but cited as Benign by reputable databases/clinical laboratories. Considering all, the variant was classified as Benign. -
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

-0.81

CADD

Benign

1.2

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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