rs200307392

Positions:

• chr2-151639945-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_001164507.2(NEB):​c.8801G>A​(p.Arg2934His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,613,890 control chromosomes in the GnomAD database, including 6 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. R2934C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 7.58

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011639535).
• BP6: Variant 2-151639945-C-T is Benign according to our data. Variant chr2-151639945-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252581.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=1}. Variant chr2-151639945-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.8801G>A	p.Arg2934His	missense_variant	62/182	ENST00000427231.7
NEB	NM_001164508.2	c.8801G>A	p.Arg2934His	missense_variant	62/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.8801G>A	p.Arg2934His	missense_variant	62/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.8801G>A	p.Arg2934His	missense_variant	62/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8801G>A	p.Arg2934His	missense_variant	62/150	5

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000759 AC: 189 AN: 249162 Hom.: 2 AF XY: 0.000688 AC XY: 93 AN XY: 135160

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000395 AC: 577 AN: 1461674 Hom.: 6 Cov.: 31 AF XY: 0.000378 AC XY: 275 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74410

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000774 Hom.: 3

Bravo AF: 0.000438

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000730 AC: 6

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NEB: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	This variant is associated with the following publications: (PMID: 29178646) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 17, 2015

- -

NEB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.6	H;H;.;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;D;.;D;N;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.57
MVP		0.61
MPC		0.38
ClinPred		0.19	T
GERP RS		5.7
Varity_R		0.29
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200307392; hg19: chr2-152496459; COSMIC: COSV104384196;