rs201747395

chr2-151642591-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):c.8356A>G(p.Arg2786Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R2786R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.42

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.8356A>G	p.Arg2786Gly	missense_variant	60/182	ENST00000427231.7
NEB	NM_001164508.2	c.8356A>G	p.Arg2786Gly	missense_variant	60/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.8356A>G	p.Arg2786Gly	missense_variant	60/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.8356A>G	p.Arg2786Gly	missense_variant	60/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8356A>G	p.Arg2786Gly	missense_variant	60/150	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000885 AC: 22 AN: 248634 Hom.: 0 AF XY: 0.0000741 AC XY: 10 AN XY: 134890

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1460906 Hom.: 0 Cov.: 31 AF XY: 0.0000991 AC XY: 72 AN XY: 726638

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74392

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces arginine with glycine at codon 2786 of the NEB protein (p.Arg2786Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs201747395, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.8356A>G (p.R2786G) alteration is located in exon 60 (coding exon 58) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 8356, causing the arginine (R) at amino acid position 2786 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.0	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D;D;.;D;D;.;.
REVEL	Benign	0.26
Sift	Benign	0.15	T;D;.;D;T;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.
Vest4		0.73
MutPred		0.53		Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);
MVP		0.59
MPC		0.38
ClinPred		0.53	D
GERP RS		6.2
Varity_R		0.36
gMVP		0.50

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: rs201747395; hg19: chr2-152499105;