rs202017360

Positions:

• chr2-151603751-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001164508.2(NEB):​c.13081G>A​(p.Glu4361Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 151,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0035 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.851

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0210782).
• BP6: Variant 2-151603751-C-T is Benign according to our data. Variant chr2-151603751-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr2-151603751-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00258 (392/151794) while in subpopulation NFE AF= 0.00442 (300/67812). AF 95% confidence interval is 0.00401. There are 0 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.13081G>A	p.Glu4361Lys	missense_variant	86/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.13081G>A	p.Glu4361Lys	missense_variant	86/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.13081G>A	p.Glu4361Lys	missense_variant	86/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.13081G>A	p.Glu4361Lys	missense_variant	86/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11601+6058G>A		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 151676 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00206 AC: 326 AN: 157902 Hom.: 0 AF XY: 0.00206 AC XY: 171 AN XY: 83134

Gnomad AFR exome AF: 0.000604

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00269

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.00155

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00355 AC: 4932 AN: 1389958 Hom.: 3 Cov.: 32 AF XY: 0.00354 AC XY: 2428 AN XY: 685614

Gnomad4 AFR exome AF: 0.000735

Gnomad4 AMR exome AF: 0.000953

Gnomad4 ASJ exome AF: 0.0000794

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.00269

Gnomad4 NFE exome AF: 0.00407

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00258 AC: 392 AN: 151794 Hom.: 0 Cov.: 22 AF XY: 0.00219 AC XY: 163 AN XY: 74286

Gnomad4 AFR AF: 0.000945

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00442

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00280 Hom.: 0

ExAC AF: 0.00405 AC: 106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NEB: BP4, BS2 -

Nemaline myopathy 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.015	.;T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D;T;D;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.021	T;T;T;T;T
MetaSVM	Benign	-0.83	T
PROVEAN	Benign	-0.61	N;.;N;.;.
REVEL	Benign	0.095
Sift	Benign	0.13	T;.;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.32
MVP		0.62
MPC		0.29
ClinPred		0.028	T
GERP RS		0.82
gMVP		0.016

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: rs202017360; hg19: chr2-152460265; COSMIC: COSV51170428;