rs75807392

Positions:

chr2-151659169-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.5971C>T(p.His1991Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 1,598,366 control chromosomes in the GnomAD database, including 5,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 421 hom., cov: 32)

Exomes 𝑓: 0.067 ( 5061 hom. )

Consequence

NEB
NM_001164508.2 missense, splice_region

Scores

Splicing: ADA: 0.0002484

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.47

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014465153).

BP6

Variant 2-151659169-G-A is Benign according to our data. Variant chr2-151659169-G-A is described in ClinVar as [Benign]. Clinvar id is 129752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151659169-G-A is described in Lovd as [Likely_benign]. Variant chr2-151659169-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/150	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0545

AC:

8278

AN:

151952

Hom.:

423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.270

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0939

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0546

Gnomad OTH

AF:

0.0411

GnomAD3 exomes

AF:

0.0772

AC:

19116

AN:

247700

Hom.:

1208

AF XY:

0.0788

AC XY:

10586

AN XY:

134346

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.0465

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.257

Gnomad SAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.0990

Gnomad NFE exome

AF:

0.0567

Gnomad OTH exome

AF:

0.0675

GnomAD4 exome

AF:

0.0670

AC:

96971

AN:

1446296

Hom.:

5061

Cov.:

AF XY:

0.0684

AC XY:

49242

AN XY:

720148

show subpopulations

Gnomad4 AFR exome

AF:

0.0163

Gnomad4 AMR exome

AF:

0.0476

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.310

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.0978

Gnomad4 NFE exome

AF:

0.0566

Gnomad4 OTH exome

AF:

0.0689

GnomAD4 genome

AF:

0.0544

AC:

8274

AN:

152070

Hom.:

421

Cov.:

AF XY:

0.0581

AC XY:

4318

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0178

Gnomad4 AMR

AF:

0.0442

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.271

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.0939

Gnomad4 NFE

AF:

0.0545

Gnomad4 OTH

AF:

0.0416

Alfa

AF:

0.0585

Hom.:

613

Bravo

AF:

0.0488

TwinsUK

AF:

0.0539

AC:

200

ALSPAC

AF:

0.0535

AC:

206

ESP6500AA

AF:

0.0158

AC:

ESP6500EA

AF:

0.0540

AC:

442

ExAC

AF:

0.0772

AC:

9322

EpiCase

AF:

0.0467

EpiControl

AF:

0.0486

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.His1991Tyr in exon 47 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 5.4% (442/8180) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/) and in 26% (148/572) of Asian chromosomes by the 1000 Genomes Project (d bSNP rs75807392). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	Variant summary: The NEB c.5971C>T (p.His1991Tyr) variant involves the alteration of a non-conserved nucleotide that is the first exonic nucleotide at an exon-intron junction. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index) and 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 20328/251662 control chromosomes (1289 homozygotes) at a frequency of 0.080775, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), strongly suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Nemaline myopathy 2

Benign:4

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Arthrogryposis multiplex congenita 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.44

DEOGEN2

Benign

0.030

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

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.064

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.12

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

M_CAP

Benign

0.018

MetaRNN

Benign

0.0014

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;.;L;L;L;L

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;N;.;N;N;.;.

REVEL

Benign

0.049

Sift

Benign

1.0

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

Sift4G

Benign

0.077

T;D;D;D;T;D;D

Polyphen

0.68

.;.;.;.;P;.;.

Vest4

0.33

MPC

0.058

ClinPred

0.030

GERP RS

4.4

Varity_R

0.043

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.046

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