rs2288211

Positions:

• chr2-151565573-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.18294T>C​(p.Tyr6098Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,590,154 control chromosomes in the GnomAD database, including 69,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5698 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63957 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-151565573-A-G is Benign according to our data. Variant chr2-151565573-A-G is described in ClinVar as [Benign]. Clinvar id is 95108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151565573-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	116/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	116/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	116/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	116/182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38006 AN: 152078 Hom.: 5701 Cov.: 32

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.271

GnomAD3 exomes AF: 0.287 AC: 69058 AN: 240454 Hom.: 10654 AF XY: 0.283 AC XY: 36798 AN XY: 130178

Gnomad AFR exome AF: 0.0816

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.307

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.291 AC: 419159 AN: 1437958 Hom.: 63957 Cov.: 31 AF XY: 0.289 AC XY: 207051 AN XY: 715828

Gnomad4 AFR exome AF: 0.0775

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.346

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.250 AC: 38005 AN: 152196 Hom.: 5698 Cov.: 32 AF XY: 0.252 AC XY: 18753 AN XY: 74426

Gnomad4 AFR AF: 0.0873

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.268

Alfa AF: 0.297 Hom.: 13248

Bravo AF: 0.252

Asia WGS AF: 0.214 AC: 749 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Tyr6098Tyr in exon 116 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 29% (2380/8182) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2288211). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.18294T>C (p.Tyr6098Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 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 30819/104302 control chromosomes (4493 homozygotes) at a frequency of 0.2954785, which is approximately 84 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	-0.59
CADD	Benign	1.6
DANN	Benign	0.61

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: rs2288211; hg19: chr2-152422087; COSMIC: COSV50873501;