2-151636282-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001164507.2(NEB):c.9047G>A(p.Arg3016Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,609,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3016G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.15

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041983962).
• BP6: Variant 2-151636282-C-T is Benign according to our data. Variant chr2-151636282-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451307.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9047G>A	p.Arg3016Gln	missense_variant	64/182	ENST00000427231.7
NEB	NM_001164508.2	c.9047G>A	p.Arg3016Gln	missense_variant	64/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9047G>A	p.Arg3016Gln	missense_variant	64/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9047G>A	p.Arg3016Gln	missense_variant	64/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8853+3611G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000569 AC: 140 AN: 246174 Hom.: 0 AF XY: 0.000605 AC XY: 81 AN XY: 133848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00168

Gnomad SAS exome AF: 0.000818

Gnomad FIN exome AF: 0.0000528

Gnomad NFE exome AF: 0.000532

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000464 AC: 676 AN: 1457658 Hom.: 0 Cov.: 31 AF XY: 0.000476 AC XY: 345 AN XY: 725262

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.0000605

Gnomad4 NFE exome AF: 0.000412

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000574 Hom.: 0

Bravo AF: 0.000586

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000621 AC: 75

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2023	- -

Nemaline myopathy 2 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.0021
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.91	D;D;D;.;.
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.042	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.66	D;D;D;D
PROVEAN	Benign	-1.5	N;.;N;.;.
REVEL	Benign	0.20
Sift	Benign	0.081	T;.;T;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Vest4		0.70
MVP		0.36
MPC		0.36
ClinPred		0.10	T
GERP RS		6.0
gMVP		0.025

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: rs373587647; hg19: chr2-152492796; COSMIC: COSV99425254;