rs45612241

Variant names:

• chr2-151583609-T-A
• rs45612241
• NM_001164507.2:c.15821A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151583609-T-A
• chr2-151583609-T-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

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. 12/17 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
• Publications: 0 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 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 Benign/Likely_benign. ClinVar VariationId is 257755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.15821A>T	p.Asn5274Ile	missense_variant	Exon 101 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.15821A>T	p.Asn5274Ile	missense_variant	Exon 101 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.15821A>T	p.Asn5274Ile	missense_variant	Exon 101 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.15821A>T	p.Asn5274Ile	missense_variant	Exon 101 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000413693.5	c.11A>T	p.Asn4Ile	missense_variant	Exon 1 of 74	5		ENSP00000410961.1
NEB	ENST00000409198.5	c.11602-7255A>T		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 311 AN: 22738 Hom.: 10 Cov.: 5

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

GnomAD2 exomes AF: 0.0183 AC: 803 AN: 43820 AF XY: 0.0187

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 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

African (AFR) AF: 0.00345 AC: 40 AN: 11586

American (AMR) AF: 0.0106 AC: 174 AN: 16462

Ashkenazi Jewish (ASJ) AF: 0.00695 AC: 84 AN: 12090

East Asian (EAS) AF: 0.000132 AC: 3 AN: 22706

South Asian (SAS) AF: 0.0114 AC: 446 AN: 39172

European-Finnish (FIN) AF: 0.0252 AC: 602 AN: 23916

Middle Eastern (MID) AF: 0.00699 AC: 12 AN: 1716

European-Non Finnish (NFE) AF: 0.0305 AC: 6967 AN: 228634

Other (OTH) AF: 0.0221 AC: 487 AN: 22038

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

African (AFR) AF: 0.00478 AC: 35 AN: 7328

American (AMR) AF: 0.0115 AC: 23 AN: 1994

Ashkenazi Jewish (ASJ) AF: 0.00649 AC: 4 AN: 616

East Asian (EAS) AF: 0.00165 AC: 1 AN: 606

South Asian (SAS) AF: 0.0104 AC: 7 AN: 672

European-Finnish (FIN) AF: 0.0203 AC: 23 AN: 1132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.0221 AC: 216 AN: 9758

Other (OTH) AF: 0.00599 AC: 2 AN: 334

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

Dec 01, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.021	.;T;.;T;.;.
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
PhyloP100		1.1
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
PromoterAI		0.012	Neutral
gMVP		0.011
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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