rs140688592

chr2-151570566-C-Achr2-151570566-C-T

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.17049G>T(p.Ala5683=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,605,778 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A5683A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (95 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0360

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-151570566-C-A is Benign according to our data. Variant chr2-151570566-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 257770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151570566-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.036 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00683 (1039/152176) while in subpopulation NFE AF= 0.0106 (724/68018). AF 95% confidence interval is 0.01. There are 6 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.17049G>T	p.Ala5683=	synonymous_variant	108/182	ENST00000427231.7
NEB	NM_001164508.2	c.17049G>T	p.Ala5683=	synonymous_variant	108/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.17049G>T	p.Ala5683=	synonymous_variant	108/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.17049G>T	p.Ala5683=	synonymous_variant	108/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11946G>T	p.Ala3982=	synonymous_variant	81/150	5
NEB	ENST00000413693.5	c.1239G>T	p.Ala413=	synonymous_variant	8/74	5

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1039 AN: 152062 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00937

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00649 AC: 1520 AN: 234334 Hom.: 7 AF XY: 0.00678 AC XY: 858 AN XY: 126592

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.0000589

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00991 AC: 14406 AN: 1453602 Hom.: 95 Cov.: 33 AF XY: 0.00981 AC XY: 7080 AN XY: 722080

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00533

Gnomad4 ASJ exome AF: 0.00622

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00511

Gnomad4 FIN exome AF: 0.00219

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00827

GnomAD4 genome AF: 0.00683 AC: 1039 AN: 152176 Hom.: 6 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74408

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00936

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00570 Hom.: 0

Bravo AF: 0.00692

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 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	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

NEB: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	3.2
Dann	Benign	0.49

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: rs140688592; hg19: chr2-152427080;