rs142454476

Positions:

• chr2-151524519-C-G

Variant summary

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

The NM_001164507.2(NEB):​c.22370G>C​(p.Ser7457Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,613,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 7.90

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22906187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.22370G>C	p.Ser7457Thr	missense_variant	152/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.22370G>C	p.Ser7457Thr	missense_variant	152/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.22370G>C	p.Ser7457Thr	missense_variant	152/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.22370G>C	p.Ser7457Thr	missense_variant	152/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000632

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000301 AC: 75 AN: 249032 Hom.: 0 AF XY: 0.000341 AC XY: 46 AN XY: 135084

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000600 AC: 877 AN: 1461654 Hom.: 1 Cov.: 33 AF XY: 0.000593 AC XY: 431 AN XY: 727110

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000760

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74488

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000737 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000952 AC: 8

ExAC AF: 0.000364 AC: 44

EpiCase AF: 0.000872

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2022	PM2 -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2022	- -

Nemaline myopathy 2 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 02, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;.;T;.;T;T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.75	T;D;D;D;T;T;.;.
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.013	D;T;.;T;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.
Vest4		0.77
MVP		0.87
MPC		0.31
ClinPred		0.16	T
GERP RS		5.9
Varity_R		0.37
gMVP		0.79

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: rs142454476; hg19: chr2-152381033;