rs201707021

Positions:

chr2-151640027-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1

The NM_001164508.2(NEB):c.8719G>A(p.Gly2907Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 7.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0702765).

BP6

Variant 2-151640027-C-T is Benign according to our data. Variant chr2-151640027-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198321.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000972 (148/152290) while in subpopulation AFR AF= 0.0033 (137/41572). AF 95% confidence interval is 0.00285. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.8719G>A	p.Gly2907Ser	missense_variant	62/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.8719G>A	p.Gly2907Ser	missense_variant	62/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.8719G>A	p.Gly2907Ser	missense_variant	62/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.8719G>A	p.Gly2907Ser	missense_variant	62/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.8719G>A	p.Gly2907Ser	missense_variant	62/150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000301

AC:

AN:

249012

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

135072

show subpopulations

Gnomad AFR exome

AF:

0.00368

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000975

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461612

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00409

Gnomad4 AMR exome

AF:

0.000134

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:

0.0000836

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000972

AC:

148

AN:

152290

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000241

Hom.:

Bravo

AF:

0.00116

ESP6500AA

AF:

0.00292

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2019	- -

Nemaline myopathy 2

Uncertain:1Benign:1

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

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.8719G>A (p.G2907S) alteration is located in exon 62 (coding exon 60) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 8719, causing the glycine (G) at amino acid position 2907 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NEB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.0050

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;.;T;.;T;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D;D;.;.

M_CAP

Benign

0.053

MetaRNN

Benign

0.070

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.028

MutationAssessor

Pathogenic

3.6

H;H;.;H;H;H;H

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.4

N;D;.;D;N;.;.

REVEL

Uncertain

0.54

Sift

Benign

0.17

T;D;.;D;T;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;.;.

Vest4

0.88

MVP

0.64

MPC

0.34

ClinPred

0.17

GERP RS

5.5

Varity_R

0.39

gMVP

0.54

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

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