rs201111610

Positions:

• chr2-151579405-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001164508.2(NEB):​c.16637G>A​(p.Arg5546His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.012 (12 hom., cov: 19)
  • Exomes 𝑓: 0.0020 (589 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.79

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03037572).
• BP6: Variant 2-151579405-C-T is Benign according to our data. Variant chr2-151579405-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257765.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr2-151579405-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16637G>A	p.Arg5546His	missense_variant	105/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16637G>A	p.Arg5546His	missense_variant	105/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16637G>A	p.Arg5546His	missense_variant	105/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.16637G>A	p.Arg5546His	missense_variant	105/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000413693.5	c.827G>A	p.Arg276His	missense_variant	5/74	5		ENSP00000410961.1
NEB	ENST00000409198.5	c.11602-3051G>A		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1669 AN: 136432 Hom.: 12 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00453

Gnomad SAS AF: 0.00490

Gnomad FIN AF: 0.00752

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.00966

GnomAD3 exomes AF: 0.000925 AC: 143 AN: 154636 Hom.: 47 AF XY: 0.000770 AC XY: 63 AN XY: 81786

Gnomad AFR exome AF: 0.00100

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000934

Gnomad SAS exome AF: 0.000708

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00199 AC: 2701 AN: 1356718 Hom.: 589 Cov.: 32 AF XY: 0.00200 AC XY: 1336 AN XY: 669282

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00214

Gnomad4 ASJ exome AF: 0.000240

Gnomad4 EAS exome AF: 0.00160

Gnomad4 SAS exome AF: 0.000678

Gnomad4 FIN exome AF: 0.00366

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0122 AC: 1669 AN: 136554 Hom.: 12 Cov.: 19 AF XY: 0.0111 AC XY: 734 AN XY: 66370

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00757

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.00454

Gnomad4 SAS AF: 0.00490

Gnomad4 FIN AF: 0.00752

Gnomad4 NFE AF: 0.0157

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.0189 Hom.: 38

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	This variant is associated with the following publications: (PMID: 25203624) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Peripheral neuropathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Claritas Genomics

Aug 22, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.0089	.;T;.;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.63	T;T;T;T;.;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.030	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.37	N;.;N;N;.;.
REVEL	Benign	0.054
Sift	Benign	0.64	T;.;T;T;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T
Vest4		0.16
MVP		0.15
MPC		0.061
ClinPred		0.0063	T
GERP RS		2.6
gMVP		0.020

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201111610; hg19: chr2-152435919;