rs117048449

chr2-151678031-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.3412A>G(p.Asn1138Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,613,996 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (110 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.58

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003719896).
• BP6: Variant 2-151678031-T-C is Benign according to our data. Variant chr2-151678031-T-C is described in ClinVar as [Benign]. Clinvar id is 129740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151678031-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	ENST00000427231.7
NEB	NM_001164508.2	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.3412A>G	p.Asn1138Asp	missense_variant	33/150	5

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 643 AN: 152176 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00880 AC: 2193 AN: 249156 Hom.: 52 AF XY: 0.00815 AC XY: 1101 AN XY: 135168

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0769

Gnomad SAS exome AF: 0.00239

Gnomad FIN exome AF: 0.00691

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00302 AC: 4408 AN: 1461702 Hom.: 110 Cov.: 31 AF XY: 0.00297 AC XY: 2157 AN XY: 727134

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0654

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00794

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.00422 AC: 642 AN: 152294 Hom.: 16 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74462

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0687

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00348 Hom.: 40

Bravo AF: 0.00468

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.000483 AC: 4

ExAC AF: 0.00815 AC: 985

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
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. -

Nemaline myopathy 2 Benign:3

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The NEB c.3412A>G (p.Asn1138Asp) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 982/120580 control chromosomes (26 homozygotes) from ExAC at a frequency of 0.008144, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant is more common in East Asian sub-population with allele frequency of 7.57% (652/8602 chromosomes). In one case-control study, this variant did not confer increased risk for prostate cancer (Haiman_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;.
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M;M
MutationTaster	Benign	0.72	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;N;.;N;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.20	T;T;.;T;T;.;.
Sift4G	Uncertain	0.037	D;D;D;D;D;D;D
Polyphen		0.95	.;.;.;.;P;.;.
Vest4		0.54
MVP		0.49
MPC		0.11
ClinPred		0.057	T
GERP RS		5.6
Varity_R		0.22
gMVP		0.38

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: rs117048449; hg19: chr2-152534545; COSMIC: COSV50874596;