rs3821324

chr2-151485796-G-Achr2-151485796-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001164507.2(NEB):c.25542C>T(p.Thr8514=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,612,818 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T8514T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.22

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-151485796-G-A is Benign according to our data. Variant chr2-151485796-G-A is described in ClinVar as [Benign]. Clinvar id is 194578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00237 (361/152264) while in subpopulation EAS AF= 0.0457 (237/5182). AF 95% confidence interval is 0.041. There are 9 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.25542C>T	p.Thr8514=	synonymous_variant	182/182	ENST00000427231.7
NEB	NM_001164508.2	c.25542C>T	p.Thr8514=	synonymous_variant	182/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.25542C>T	p.Thr8514=	synonymous_variant	182/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.25542C>T	p.Thr8514=	synonymous_variant	182/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152146 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0464

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00543 AC: 1348 AN: 248224 Hom.: 24 AF XY: 0.00503 AC XY: 677 AN XY: 134546

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0484

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000383

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00161 AC: 2357 AN: 1460554 Hom.: 32 Cov.: 31 AF XY: 0.00154 AC XY: 1122 AN XY: 726380

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00969

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0311

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152264 Hom.: 9 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74454

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0457

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.00321

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.000657

EpiControl AF: 0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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)	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The c.25647C>T (p.Thr8549=) in NEB gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control population dataset of ExAC at a frequency of 0.0049 (593/120504 chrs tested), predominantly in individuals of East Asian descent (0.047; 403/8622chrs tested, including 12 homozygotes). These frequencies exceed the estimated maximal expected allele frequency of a pathogenic variant in NEB gene (0.0035). Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Benign. Taking together, the variant was classified as Benign. -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	1.9
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: rs3821324; hg19: chr2-152342310; COSMIC: COSV51426418; COSMIC: COSV51426418;