rs202191938

Positions:

• chr2-151506167-G-A
• chr2-151506167-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_001164507.2(NEB):​c.23648C>T​(p.Ser7883Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,607,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 7.59

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-151506167-G-A is Benign according to our data. Variant chr2-151506167-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95119.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.23648C>T	p.Ser7883Leu	missense_variant, splice_region_variant	164/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.23648C>T	p.Ser7883Leu	missense_variant, splice_region_variant	164/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.23648C>T	p.Ser7883Leu	missense_variant, splice_region_variant	164/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.23648C>T	p.Ser7883Leu	missense_variant, splice_region_variant	164/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 249172 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135164

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000869

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: 0.0000974

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.0000804 AC: 117 AN: 1455076 Hom.: 0 Cov.: 29 AF XY: 0.0000953 AC XY: 69 AN XY: 724268

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000534

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74504

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Olimpia_2023) -

Nemaline myopathy 2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -

NEB-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2023

The NEB c.23753C>T variant is predicted to result in the amino acid substitution p.Ser7918Leu. This variant has been reported with uncertain significance in the heterozygous state, along with variants in other genes, in an individual with myofibrillar myopathy (Case 1, Carbunar O, M Saporta, and S Gultekin. 2023. doi:10.17161/rrnmf.v4i2.18512). This variant is reported in 0.088% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152362681-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;.;T;.;T;T;.;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.38	T;T;D;T;T;T;.;.;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.048	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;D;.;N;N;D;.;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.020	D;D;.;D;D;D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;.
Polyphen		0.47	.;.;.;.;P;.;.;.;.
Vest4		0.38
MutPred		0.41		Loss of disorder (P = 0.0133);.;.;.;Loss of disorder (P = 0.0133);.;.;.;.;
MVP		0.61
MPC		0.070
ClinPred		0.23	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.040		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: rs202191938; hg19: chr2-152362681; COSMIC: COSV99416974;