rs886038429

chr2-151604714-T-Achr2-151604714-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001164507.2(NEB):c.12905A>T(p.Asn4302Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N4302N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 5)
  • Exomes 𝑓: 0.0020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.31

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20436049).
• BP6: Variant 2-151604714-T-A is Benign according to our data. Variant chr2-151604714-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257727.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr2-151604714-T-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.12905A>T	p.Asn4302Ile	missense_variant	85/182	ENST00000427231.7
NEB	NM_001164508.2	c.12905A>T	p.Asn4302Ile	missense_variant	85/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.12905A>T	p.Asn4302Ile	missense_variant	85/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.12905A>T	p.Asn4302Ile	missense_variant	85/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+5095A>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8 AN: 30424 Hom.: 0 Cov.: 5 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000414

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: 0.000404

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000460 AC: 23 AN: 50012 Hom.: 0 AF XY: 0.000513 AC XY: 13 AN XY: 25364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000988

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00204 AC: 833 AN: 408430 Hom.: 0 Cov.: 3 AF XY: 0.00198 AC XY: 426 AN XY: 214994

Gnomad4 AFR exome AF: 0.000558

Gnomad4 AMR exome AF: 0.000727

Gnomad4 ASJ exome AF: 0.000552

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.00209

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000263 AC: 8 AN: 30434 Hom.: 0 Cov.: 5 AF XY: 0.000221 AC XY: 3 AN XY: 13588

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000413

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000404

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000789 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2018	This sequence change replaces asparagine with isoleucine at codon 4302 of the NEB protein (p.Asn4302Ile). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a NEB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "probably damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. Missense variants in the NEB gene are typically not pathogenic, and there is no indication that this variant causes disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2021

This variant is associated with the following publications: (PMID: 25205138) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.35
Dann	Benign	0.89
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.57	T;T;T;.;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-2.0	N;.;N;.;.
REVEL	Benign	0.086
Sift	Uncertain	0.012	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.45
MutPred		0.53		Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);
MVP		0.44
MPC		0.36
ClinPred		0.085	T
GERP RS		0.67
gMVP		0.0017

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: rs886038429; hg19: chr2-152461228;