2-151602679-C-T

Position:

• chr2-151602679-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001164507.2(NEB):​c.13276G>A​(p.Asp4426Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 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 0.00039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000089 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.70

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21040237).
• BP6: Variant 2-151602679-C-T is Benign according to our data. Variant chr2-151602679-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227726.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr2-151602679-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.13276G>A	p.Asp4426Asn	missense_variant	87/182	ENST00000427231.7
NEB	NM_001164508.2	c.13276G>A	p.Asp4426Asn	missense_variant	87/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.13276G>A	p.Asp4426Asn	missense_variant	87/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.13276G>A	p.Asp4426Asn	missense_variant	87/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+7130G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 5074 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000249

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000889 AC: 6 AN: 67488 Hom.: 1 Cov.: 0 AF XY: 0.0000840 AC XY: 3 AN XY: 35698

Gnomad4 AFR exome AF: 0.00806

Gnomad4 AMR exome AF: 0.000489

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000956

Gnomad4 SAS exome AF: 0.000494

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000214

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000394 AC: 2 AN: 5076 Hom.: 0 Cov.: 0 AF XY: 0.000432 AC XY: 1 AN XY: 2314

Gnomad4 AFR AF: 0.00581

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000249

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000769 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2014	NEB exons 82-105 are organized in three repetitive blocks of 8 exons each and be cause these blocks are nearly identical in sequence, homologous exons (e.g., exo ns 82, 90, and 98) are co-amplified and sequenced (each amplicon consists of 6 a lleles). This variant represents a nonhomologous position within the three repet itive blocks (c.13276G, c.14734A, and c.16192G). The variable alleles at this po sition are not expected to have clinical significance due to a lack of conservat ion at this position across species, including mammals. A change at this positio n has also been identified in 0.4% (41/10774) to 15% (3900/21678) of chromosomes across several diverse populations by the Exome Aggregate Consortium (http://ex ac.broadinstitute.org/). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Uncertain	24
DANN	Benign	0.82
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.15	T;T;T;.;.
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.30	N;.;N;.;.
REVEL	Benign	0.040
Sift	Uncertain	0.011	D;.;D;.;.
Sift4G	Uncertain	0.010	D;D;D;D;D
Vest4		0.16
MutPred		0.33		Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);
MVP		0.56
MPC		0.31
ClinPred		0.21	T
GERP RS		3.5
gMVP		0.0081

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: rs876657540; hg19: chr2-152459193;