rs118191309

Positions:

chr2-151506216-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164508.2(NEB):c.23599A>C(p.Lys7867Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,806 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 30 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.90

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:

RIF1 (HGNC:):

RIF1 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=0.004918307).

BP6

Variant 2-151506216-T-G is Benign according to our data. Variant chr2-151506216-T-G is described in ClinVar as [Benign]. Clinvar id is 194308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151506216-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00225 (343/152370) while in subpopulation EAS AF= 0.0442 (229/5182). AF 95% confidence interval is 0.0395. There are 8 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	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.23599A>C	p.Lys7867Gln	missense_variant	164/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

346

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0449

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00526

AC:

1311

AN:

249152

Hom.:

AF XY:

0.00484

AC XY:

654

AN XY:

135150

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0473

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00155

AC:

2266

AN:

1461436

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1074

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00932

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0307

Gnomad4 SAS exome

AF:

0.00187

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000200

Gnomad4 OTH exome

AF:

0.00388

GnomAD4 genome

AF:

0.00225

AC:

343

AN:

152370

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00385

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0442

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000864

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00478

AC:

578

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The NEB c.23704A>C (p.Lys7902Gln) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/4 in silico tools. This variant was found in 578/120716 control chromosomes (13 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.045908 (396/8626). This frequency is about 13 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.025

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

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

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

MetaRNN

Benign

0.0049

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.41

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

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.36

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

REVEL

Benign

0.082

Sift

Benign

0.28

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

Sift4G

Benign

0.20

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

Polyphen

0.0020

.;.;.;.;B;.;.;.;.

Vest4

0.27

MVP

0.43

MPC

0.075

ClinPred

0.011

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.23

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