rs2288195

Positions:

chr2-151492512-G-A

Variant summary

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

The NM_001164507.2(NEB):c.24766-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,564,944 control chromosomes in the GnomAD database, including 347,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32323 hom., cov: 28)

Exomes 𝑓: 0.67 ( 315478 hom. )

Consequence

NEB
NM_001164507.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0570

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-151492512-G-A is Benign according to our data. Variant chr2-151492512-G-A is described in ClinVar as [Benign]. Clinvar id is 95122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151492512-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.24766-18C>T		intron_variant		ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.24766-18C>T		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.24766-18C>T		intron_variant		5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.24766-18C>T		intron_variant		5	NM_001164507.2	A2	P20929-3

Frequencies

GnomAD3 genomes

AF:

0.649

AC:

98392

AN:

151604

Hom.:

32279

Cov.:

show subpopulations

Gnomad AFR

AF:

0.582

Gnomad AMI

AF:

0.590

Gnomad AMR

AF:

0.727

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.774

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.691

Gnomad MID

AF:

0.734

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.663

GnomAD3 exomes

AF:

0.668

AC:

163483

AN:

244902

Hom.:

55259

AF XY:

0.660

AC XY:

87730

AN XY:

133012

show subpopulations

Gnomad AFR exome

AF:

0.583

Gnomad AMR exome

AF:

0.762

Gnomad ASJ exome

AF:

0.640

Gnomad EAS exome

AF:

0.775

Gnomad SAS exome

AF:

0.547

Gnomad FIN exome

AF:

0.687

Gnomad NFE exome

AF:

0.664

Gnomad OTH exome

AF:

0.675

GnomAD4 exome

AF:

0.667

AC:

941975

AN:

1413222

Hom.:

315478

Cov.:

AF XY:

0.662

AC XY:

467378

AN XY:

705816

show subpopulations

Gnomad4 AFR exome

AF:

0.590

Gnomad4 AMR exome

AF:

0.754

Gnomad4 ASJ exome

AF:

0.636

Gnomad4 EAS exome

AF:

0.797

Gnomad4 SAS exome

AF:

0.552

Gnomad4 FIN exome

AF:

0.688

Gnomad4 NFE exome

AF:

0.669

Gnomad4 OTH exome

AF:

0.668

GnomAD4 genome

AF:

0.649

AC:

98500

AN:

151722

Hom.:

32323

Cov.:

AF XY:

0.653

AC XY:

48368

AN XY:

74120

show subpopulations

Gnomad4 AFR

AF:

0.582

Gnomad4 AMR

AF:

0.727

Gnomad4 ASJ

AF:

0.631

Gnomad4 EAS

AF:

0.773

Gnomad4 SAS

AF:

0.551

Gnomad4 FIN

AF:

0.691

Gnomad4 NFE

AF:

0.664

Gnomad4 OTH

AF:

0.667

Alfa

AF:

0.662

Hom.:

6819

Bravo

AF:

0.654

Asia WGS

AF:

0.652

AC:

2269

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -

Nemaline myopathy 2

Benign:2

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

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 27, 2017

Variant summary: The NEB c.24871-18C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 79288/119702 control chromosomes (26517 homozygotes) at a frequency of 0.6623782, which is approximately 187 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

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

-0.91

CADD

Benign

0.54

DANN

Benign

0.67

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