rs78733601

Positions:

• chr2-151655360-A-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.6717T>G​(p.Ile2239Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,581,574 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (80 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.03

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=0.0022902489).
• BP6: Variant 2-151655360-A-C is Benign according to our data. Variant chr2-151655360-A-C is described in ClinVar as [Benign]. Clinvar id is 129755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151655360-A-C is described in Lovd as [Benign]. Variant chr2-151655360-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.6717T>G	p.Ile2239Met	missense_variant	51/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.6717T>G	p.Ile2239Met	missense_variant	51/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.6717T>G	p.Ile2239Met	missense_variant	51/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.6717T>G	p.Ile2239Met	missense_variant	51/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.6717T>G	p.Ile2239Met	missense_variant	51/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1678 AN: 152022 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0632

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00752 AC: 1818 AN: 241768 Hom.: 34 AF XY: 0.00650 AC XY: 852 AN XY: 131024

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000405

Gnomad EAS exome AF: 0.0649

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00581

GnomAD4 exome AF: 0.00293 AC: 4194 AN: 1429434 Hom.: 80 Cov.: 26 AF XY: 0.00287 AC XY: 2042 AN XY: 711646

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.000272

Gnomad4 EAS exome AF: 0.0541

Gnomad4 SAS exome AF: 0.00224

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.00674

GnomAD4 genome AF: 0.0111 AC: 1683 AN: 152140 Hom.: 36 Cov.: 32 AF XY: 0.0112 AC XY: 833 AN XY: 74382

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0633

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00532 Hom.: 39

Bravo AF: 0.0127

ESP6500AA AF: 0.0270 AC: 98

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.00766 AC: 924

Asia WGS AF: 0.0470 AC: 162 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nemaline myopathy 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.010	.;.;T;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	T;D;D;D;T;.;.
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;.;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.27	N;N;.;N;N;.;.
REVEL	Benign	0.061
Sift	Benign	0.13	T;T;.;T;T;.;.
Sift4G	Uncertain	0.057	T;T;T;T;T;T;T
Polyphen		0.085	.;.;.;.;B;.;.
Vest4		0.22
MVP		0.44
MPC		0.19
ClinPred		0.031	T
GERP RS		3.5
Varity_R		0.060
gMVP		0.11

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: rs78733601; hg19: chr2-152511874; COSMIC: COSV50812550;