rs202048855

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001164507.2(NEB):c.24579G>C(p.Ser8193=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,601,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S8193S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

NEB
NM_001164507.2 splice_region, synonymous

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.22

Variant links:

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]

NEB links:

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]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-151494161-C-G is Pathogenic according to our data. Variant chr2-151494161-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 657591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151494161-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.24579G>C	p.Ser8193=	splice_region_variant, synonymous_variant	174/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.24579G>C	p.Ser8193=	splice_region_variant, synonymous_variant	174/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.24579G>C	p.Ser8193=	splice_region_variant, synonymous_variant	174/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.24579G>C	p.Ser8193=	splice_region_variant, synonymous_variant	174/182	5	NM_001164507.2	A2	P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000857

AC:

AN:

233398

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126034

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000407

AC:

AN:

1449934

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

720014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00147

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change affects codon 8228 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs202048855, gnomAD 0.01%). This variant has been observed in individual(s) with nemaline myopathy (PMID: 30467404). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 657591). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in intron 175 retention and introduces a premature termination codon (PMID: 30467404). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.24684G nucleotide in the NEB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 24725366, 29669168). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Arthrogryposis multiplex congenita 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.59

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over