rs201169452

Positions:

chr2-151672462-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_001164507.2(NEB):c.4206T>A(p.Asn1402Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,972 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 3 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.127

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00810039).

BP6

Variant 2-151672462-A-T is Benign according to our data. Variant chr2-151672462-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257814.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00148 (226/152288) while in subpopulation AFR AF= 0.0052 (216/41560). AF 95% confidence interval is 0.00463. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.4206T>A	p.Asn1402Lys	missense_variant	37/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.4206T>A	p.Asn1402Lys	missense_variant	37/182	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.4206T>A	p.Asn1402Lys	missense_variant	37/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.4206T>A	p.Asn1402Lys	missense_variant	37/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.4206T>A	p.Asn1402Lys	missense_variant	37/150	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00519

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:

0.00143

GnomAD3 exomes

AF:

0.000369

AC:

AN:

249234

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.00581

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000192

AC:

281

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00780

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.00148

AC:

226

AN:

152288

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00520

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:

0.00142

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.00192

ESP6500AA

AF:

0.00387

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000471

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.5

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

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

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.0081

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

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

M;M;.;M;M;M;M

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.13

Sift

Benign

0.085

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

Sift4G

Uncertain

0.012

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

Polyphen

0.97

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

Vest4

0.65

MutPred

0.49

Gain of methylation at N1402 (P = 0.0189);Gain of methylation at N1402 (P = 0.0189);Gain of methylation at N1402 (P = 0.0189);Gain of methylation at N1402 (P = 0.0189);Gain of methylation at N1402 (P = 0.0189);Gain of methylation at N1402 (P = 0.0189);Gain of methylation at N1402 (P = 0.0189);

MVP

0.24

MPC

0.29

ClinPred

0.076

GERP RS

-5.2

Varity_R

0.11

gMVP

0.48

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