rs184262608

Positions:

chr2-151659071-C-T

Variant summary

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

The NM_001164508.2(NEB):c.6069G>A(p.Met2023Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,596,242 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 66 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.968

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=0.011434644).

BP6

Variant 2-151659071-C-T is Benign according to our data. Variant chr2-151659071-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151659071-C-T is described in Lovd as [Benign]. Variant chr2-151659071-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00648 (987/152244) while in subpopulation NFE AF= 0.0105 (714/68030). AF 95% confidence interval is 0.00986. There are 8 homozygotes in gnomad4. There are 485 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.6069G>A	p.Met2023Ile	missense_variant	47/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.6069G>A	p.Met2023Ile	missense_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.6069G>A	p.Met2023Ile	missense_variant	47/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.6069G>A	p.Met2023Ile	missense_variant	47/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.6069G>A	p.Met2023Ile	missense_variant	47/150	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00649

AC:

987

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00764

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00642

AC:

1598

AN:

248750

Hom.:

AF XY:

0.00640

AC XY:

864

AN XY:

134922

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00808

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00779

GnomAD4 exome

AF:

0.00845

AC:

12198

AN:

1443998

Hom.:

Cov.:

AF XY:

0.00828

AC XY:

5958

AN XY:

719402

show subpopulations

Gnomad4 AFR exome

AF:

0.00139

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.00354

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00137

Gnomad4 FIN exome

AF:

0.00770

Gnomad4 NFE exome

AF:

0.0100

Gnomad4 OTH exome

AF:

0.00737

GnomAD4 genome

AF:

0.00648

AC:

987

AN:

152244

Hom.:

Cov.:

AF XY:

0.00652

AC XY:

485

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00764

Gnomad4 NFE

AF:

0.0105

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00935

Hom.:

Bravo

AF:

0.00568

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00134

AC:

ESP6500EA

AF:

0.00999

AC:

ExAC

AF:

0.00650

AC:

785

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00939

EpiControl

AF:

0.00842

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NEB: BS1, BS2 -

Nemaline myopathy 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.013

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

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.67

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

MetaRNN

Benign

0.011

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.28

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

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.89

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

REVEL

Benign

0.13

Sift

Benign

1.0

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

Sift4G

Benign

0.94

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

Polyphen

0.0

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

Vest4

0.25

MutPred

0.60

Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.25

MPC

0.056

ClinPred

0.012

GERP RS

5.2

Varity_R

0.29

gMVP

0.21

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