rs4414676

Positions:

• chr2-151491671-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.25150+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,565,382 control chromosomes in the GnomAD database, including 2,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (1119 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (1102 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-151491671-C-T is Benign according to our data. Variant chr2-151491671-C-T is described in ClinVar as [Benign]. Clinvar id is 226845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151491671-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.25150+12G>A		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.25150+12G>A		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.25150+12G>A		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.25150+12G>A		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10216 AN: 152098 Hom.: 1118 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0592

GnomAD3 exomes AF: 0.0163 AC: 3208 AN: 196570 Hom.: 341 AF XY: 0.0124 AC XY: 1292 AN XY: 104340

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000664

Gnomad OTH exome AF: 0.00893

GnomAD4 exome AF: 0.00719 AC: 10159 AN: 1413166 Hom.: 1102 Cov.: 29 AF XY: 0.00624 AC XY: 4367 AN XY: 699792

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.0000788

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000632

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000454

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0672 AC: 10231 AN: 152216 Hom.: 1119 Cov.: 32 AF XY: 0.0641 AC XY: 4771 AN XY: 74430

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0407 Hom.: 151

Bravo AF: 0.0784

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	25255+12G>A in intron 180 of NEB: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 22.3% (846/3802) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs4414676). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 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	Apr 13, 2016	- -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.9
DANN	Benign	0.82

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

Other links and lift over

dbSNP: rs4414676; hg19: chr2-152348185;