rs35707762

Positions:

chr2-151548387-G-A

Variant summary

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

The NM_001164508.2(NEB):c.20078C>T(p.Thr6693Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,613,528 control chromosomes in the GnomAD database, including 121 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 0.0072 ( 12 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.36

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=0.0039313436).

BP6

Variant 2-151548387-G-A is Benign according to our data. Variant chr2-151548387-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151548387-G-A is described in Lovd as [Benign]. Variant chr2-151548387-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00725 (1104/152304) while in subpopulation NFE AF= 0.0117 (795/68022). AF 95% confidence interval is 0.011. There are 12 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	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.20078C>T	p.Thr6693Ile	missense_variant	131/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00726

AC:

1105

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00989

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00714

AC:

1778

AN:

248948

Hom.:

AF XY:

0.00738

AC XY:

997

AN XY:

135042

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00701

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00441

Gnomad FIN exome

AF:

0.000835

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00861

GnomAD4 exome

AF:

0.0106

AC:

15493

AN:

1461224

Hom.:

109

Cov.:

AF XY:

0.0103

AC XY:

7478

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.00751

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00463

Gnomad4 FIN exome

AF:

0.00142

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.00785

GnomAD4 genome

AF:

0.00725

AC:

1104

AN:

152304

Hom.:

Cov.:

AF XY:

0.00670

AC XY:

499

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00260

Gnomad4 AMR

AF:

0.00988

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00762

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00237

AC:

ESP6500EA

AF:

0.0119

AC:

ExAC

AF:

0.00682

AC:

824

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00976

EpiControl

AF:

0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NEB: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Nemaline myopathy 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -
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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.0031

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

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.59

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

MetaRNN

Benign

0.0039

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

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

PrimateAI

Benign

0.30

PROVEAN

Benign

0.65

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

REVEL

Benign

0.19

Sift

Benign

0.71

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.18

MVP

0.36

MPC

0.054

ClinPred

0.0040

GERP RS

4.9

Varity_R

0.040

gMVP

0.13

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