rs200555425

chr2-151725488-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164507.2(NEB):c.367C>T(p.Arg123Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,613,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R123H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.67

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22308877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.367C>T	p.Arg123Cys	missense_variant	6/182	ENST00000427231.7
NEB	NM_001164508.2	c.367C>T	p.Arg123Cys	missense_variant	6/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.367C>T	p.Arg123Cys	missense_variant	6/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.367C>T	p.Arg123Cys	missense_variant	6/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.367C>T	p.Arg123Cys	missense_variant	6/150	5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 31 AN: 248746 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 134952

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000548 AC: 80 AN: 1460864 Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40 AN XY: 726688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000245 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
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

Oct 12, 2021

The c.367C>T (p.R123C) alteration is located in exon 6 (coding exon 4) of the NEB gene. This alteration results from a C to T substitution at nucleotide position 367, causing the arginine (R) at amino acid position 123 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M;M
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;D;.;D;N;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.019	D;T;.;T;D;.;.
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.69
MVP		0.66
MPC		0.38
ClinPred		0.49	T
GERP RS		6.2
Varity_R		0.22
gMVP		0.29

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: rs200555425; hg19: chr2-152582002; COSMIC: COSV50807246;