rs202050860

chr2-151524358-G-A

Variant summary

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

The NM_001164507.2(NEB):c.22432C>T(p.Arg7478Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,718 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R7478H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.99

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:):

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.22432C>T	p.Arg7478Cys	missense_variant	153/182	ENST00000427231.7
NEB	NM_001164508.2	c.22432C>T	p.Arg7478Cys	missense_variant	153/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.22432C>T	p.Arg7478Cys	missense_variant	153/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.22432C>T	p.Arg7478Cys	missense_variant	153/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000161 AC: 40 AN: 248804 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134980

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461548 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 727066

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152170 Hom.: 1 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74328

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000256 AC: 31

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nemaline myopathy 2 Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 22, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;.;.
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;D;.;D;D;D;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.024	D;D;.;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.
Vest4		0.77
MVP		0.75
MPC		0.39
ClinPred		0.22	T
GERP RS		6.1
Varity_R		0.28
gMVP		0.43

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: rs202050860; hg19: chr2-152380872;