rs144180493

chr2-151663756-A-Cchr2-151663756-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):c.5555T>G(p.Met1852Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,613,850 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1852V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (30 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 9.32

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 (MetaRNN=0.01530838).
• BP6: Variant 2-151663756-A-C is Benign according to our data. Variant chr2-151663756-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197524.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr2-151663756-A-C is described in Lovd as [Likely_benign]. Variant chr2-151663756-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00331 (504/152302) while in subpopulation NFE AF= 0.0057 (388/68028). AF 95% confidence interval is 0.00524. There are 2 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5555T>G	p.Met1852Arg	missense_variant	45/182	ENST00000427231.7
NEB	NM_001164508.2	c.5555T>G	p.Met1852Arg	missense_variant	45/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5555T>G	p.Met1852Arg	missense_variant	45/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5555T>G	p.Met1852Arg	missense_variant	45/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5555T>G	p.Met1852Arg	missense_variant	45/150	5

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00332 AC: 826 AN: 249030 Hom.: 3 AF XY: 0.00309 AC XY: 418 AN XY: 135098

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.000928

Gnomad NFE exome AF: 0.00538

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00526 AC: 7683 AN: 1461548 Hom.: 30 Cov.: 31 AF XY: 0.00515 AC XY: 3745 AN XY: 727058

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00631

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74466

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00570

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00508 Hom.: 1

Bravo AF: 0.00344

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000504 AC: 2

ESP6500EA AF: 0.00492 AC: 41

ExAC AF: 0.00329 AC: 398

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 03, 2016	p.Met1852Arg in exon 45 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (332/66652) of European chromo somes, including two homozygotes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs144180493). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NEB: BS2 -

Nemaline myopathy 2 Uncertain:1 Benign:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;T;.;T;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.72	.;.;.;.;P;.;.
Vest4		0.86
MVP		0.65
MPC		0.35
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.89
gMVP		0.60

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: rs144180493; hg19: chr2-152520270;