rs147579763

Positions:

• chr2-151603727-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001164508.2(NEB):​c.13105C>T​(p.Leu4369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (6 hom., cov: 22)
  • Exomes 𝑓: 0.000032 (19 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.28

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-151603727-G-A is Benign according to our data. Variant chr2-151603727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151603727-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.28 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.13105C>T	p.Leu4369=	synonymous_variant	86/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.13105C>T	p.Leu4369=	synonymous_variant	86/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.13105C>T	p.Leu4369=	synonymous_variant	86/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.13105C>T	p.Leu4369=	synonymous_variant	86/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+6082C>T		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00 AC: 72 AN: 150390 Hom.: 5 Cov.: 22 FAILED QC

Gnomad AFR AF: 0.00163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000966

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000322 AC: 45 AN: 1397180 Hom.: 19 Cov.: 32 AF XY: 0.0000377 AC XY: 26 AN XY: 689118

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.0000690

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000485 AC: 73 AN: 150500 Hom.: 6 Cov.: 22 AF XY: 0.000489 AC XY: 36 AN XY: 73674

Gnomad4 AFR AF: 0.00165

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00143 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2014	NEB exons 82-105 are organized in three repetitive blocks of 8 exons each and be cause these blocks are nearly identical in sequence, homologous exons (e.g., exo ns 86, 94, and 102) are co-amplified and sequenced (each amplicon consists of 6 alleles). This variant represents a nonhomologous position within the three repe titive blocks (c.13105C, c.14563T, and c.16021T) and is categorized as "Likely B enign" as all three positions code for an Leucine (p.Leu4369, p.Leu4855, p.Leu53 41). -

Nemaline myopathy 2 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.92
DANN	Benign	0.62

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: rs147579763; hg19: chr2-152460241; COSMIC: COSV50830069;