rs886038429

Variant names:

• chr2-151604714-T-A
• rs886038429
• NM_001164507.2:c.12905A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151604714-T-A
• chr2-151604714-T-C

Variant summary

Our verdict is Likely benign. The variant received -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. 13/18 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
• Publications: 0 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 257727.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.12905A>T	p.Asn4302Ile	missense	Exon 85 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.12905A>T	p.Asn4302Ile	missense	Exon 85 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.12905A>T	p.Asn4302Ile	missense	Exon 85 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.12905A>T	p.Asn4302Ile	missense	Exon 85 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12905A>T	p.Asn4302Ile	missense	Exon 85 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+5095A>T		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 8 AN: 30424 Hom.: 0 Cov.: 5

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

GnomAD2 exomes AF: 0.000460 AC: 23 AN: 50012 AF XY: 0.000513

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000558 AC: 6 AN: 10754

American (AMR) AF: 0.000727 AC: 12 AN: 16498

Ashkenazi Jewish (ASJ) AF: 0.000552 AC: 7 AN: 12686

East Asian (EAS) AF: 0.00 AC: 0 AN: 26736

South Asian (SAS) AF: 0.00191 AC: 79 AN: 41454

European-Finnish (FIN) AF: 0.00209 AC: 53 AN: 25360

Middle Eastern (MID) AF: 0.00112 AC: 2 AN: 1790

European-Non Finnish (NFE) AF: 0.00252 AC: 629 AN: 249632

Other (OTH) AF: 0.00191 AC: 45 AN: 23520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4800

American (AMR) AF: 0.000413 AC: 1 AN: 2422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 780

East Asian (EAS) AF: 0.00 AC: 0 AN: 1288

South Asian (SAS) AF: 0.00 AC: 0 AN: 842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 128

European-Non Finnish (NFE) AF: 0.000404 AC: 7 AN: 17306

Other (OTH) AF: 0.00 AC: 0 AN: 406

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

Nov 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Mar 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.35
DANN	Benign	0.89
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.3
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.086
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Vest4		0.45
MutPred		0.53		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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs886038429; hg19: chr2-152461228;