rs947053462

Variant names:

• chr2-151513653-C-T
• rs947053462
• NM_001164507.2:c.23168G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001164507.2(NEB):​c.23168G>A​(p.Arg7723Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046092838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.23168G>A	p.Arg7723Lys	missense_variant	Exon 160 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.23168G>A	p.Arg7723Lys	missense_variant	Exon 160 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.23168G>A	p.Arg7723Lys	missense_variant	Exon 160 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.23168G>A	p.Arg7723Lys	missense_variant	Exon 160 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456168 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723562

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 84526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109264

Other (OTH) AF: 0.00 AC: 0 AN: 60198

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

May 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 465570). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 7758 of the NEB protein (p.Arg7758Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.0071	.;.;T;.;T;T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;.;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-1.1	N;.;.;.;N;.;.;.
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.33	N;N;.;N;N;N;.;.
REVEL	Benign	0.073
Sift	Benign	0.88	T;T;.;T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.;.
Vest4		0.21
MutPred		0.46		Gain of ubiquitination at R6022 (P = 0.0131);.;.;.;Gain of ubiquitination at R6022 (P = 0.0131);.;.;.;
MVP		0.27
MPC		0.055
ClinPred		0.36	T
GERP RS		3.6
PromoterAI		-0.012	Neutral
Varity_R		0.090
gMVP		0.067
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs947053462; hg19: chr2-152370167;