rs77547727

chr2-151662333-G-A

Variant summary

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

The NM_001164507.2(NEB):c.5772C>T(p.Tyr1924=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,569,196 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (81 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.53

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=-0.49).
• BP6: Variant 2-151662333-G-A is Benign according to our data. Variant chr2-151662333-G-A is described in ClinVar as [Benign]. Clinvar id is 129751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151662333-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5772C>T	p.Tyr1924=	synonymous_variant	46/182	ENST00000427231.7
NEB	NM_001164508.2	c.5772C>T	p.Tyr1924=	synonymous_variant	46/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5772C>T	p.Tyr1924=	synonymous_variant	46/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5772C>T	p.Tyr1924=	synonymous_variant	46/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5772C>T	p.Tyr1924=	synonymous_variant	46/150	5

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1696 AN: 152016 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00788 AC: 1831 AN: 232462 Hom.: 34 AF XY: 0.00684 AC XY: 861 AN XY: 125882

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.000448

Gnomad EAS exome AF: 0.0662

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00595

GnomAD4 exome AF: 0.00302 AC: 4284 AN: 1417062 Hom.: 81 Cov.: 31 AF XY: 0.00298 AC XY: 2087 AN XY: 700664

Gnomad4 AFR exome AF: 0.0354

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.000285

Gnomad4 EAS exome AF: 0.0547

Gnomad4 SAS exome AF: 0.00251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00694

GnomAD4 genome AF: 0.0112 AC: 1700 AN: 152134 Hom.: 40 Cov.: 32 AF XY: 0.0113 AC XY: 842 AN XY: 74358

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0629

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00580 Hom.: 10

Bravo AF: 0.0127

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	GeneDx	Jun 20, 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:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.5
Dann	Benign	0.53

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: rs77547727; hg19: chr2-152518847; COSMIC: COSV50868447;