rs45612241

chr2-151583609-T-Achr2-151583609-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001164507.2(NEB):c.15821A>T(p.Asn5274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (10 hom., cov: 5)
  • Exomes 𝑓: 0.023 (1228 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.08

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002429992).
• BP6: Variant 2-151583609-T-A is Benign according to our data. Variant chr2-151583609-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 257755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151583609-T-A is described in Lovd as [Benign]. Variant chr2-151583609-T-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 154 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	ENST00000427231.7
NEB	NM_001164508.2	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	5	NM_001164507.2	A2
NEB	ENST00000413693.5	c.11A>T	p.Asn4Ile	missense_variant	1/74	5
NEB	ENST00000409198.5	c.11602-7255A>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 311 AN: 22738 Hom.: 10 Cov.: 5 FAILED QC

Gnomad AFR AF: 0.00481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00649

Gnomad EAS AF: 0.00163

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.00606

GnomAD3 exomes AF: 0.0183 AC: 803 AN: 43820 Hom.: 154 AF XY: 0.0187 AC XY: 415 AN XY: 22220

Gnomad AFR exome AF: 0.00420

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00683

Gnomad EAS exome AF: 0.000457

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0186

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0233 AC: 8815 AN: 378320 Hom.: 1228 Cov.: 2 AF XY: 0.0228 AC XY: 4532 AN XY: 198908

Gnomad4 AFR exome AF: 0.00345

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.00695

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0252

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0221

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0137 AC: 311 AN: 22756 Hom.: 10 Cov.: 5 AF XY: 0.0124 AC XY: 123 AN XY: 9928

Gnomad4 AFR AF: 0.00478

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00649

Gnomad4 EAS AF: 0.00165

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.00599

Alfa AF: 0.00130 Hom.: 0

ExAC AF: 0.00463 AC: 21

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.55	T;T;T;T;.;.
MetaRNN	Benign	0.0024	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.66	D;D;D;D
PROVEAN	Benign	-1.5	N;.;N;N;.;.
REVEL	Benign	0.054
Sift	Benign	0.064	T;.;D;T;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Vest4		0.52
MPC		0.36
ClinPred		0.0084	T
GERP RS		3.8
gMVP		0.011

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: rs45612241; hg19: chr2-152440123; COSMIC: COSV51080697;