rs191579691

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PP3PP4PS3

This summary comes from the ClinGen Evidence Repository: The c.19097G>T (p.Ser6366Ile) variant in NEB is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 6366. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004723 (30/63518 alleles) in the European (Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1. However, this variant is excluded from the application of BA1/BS1 by the ClinGen Congenital Myopathies VCEP as it is a well established pathogenic variant. The computational predictor REVEL gives a score of 0.829, which is above the threshold of 0.7, evidence that correlates with impact to NEB function (PP3). This variant has been detected in 10 individuals with nemaline myopathy. Eight of those individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 2 of those were confirmed in trans by family testing. Two individuals were homozygous for the variant (PMIDs: 25205138, 15336686, 17525139) (PM3_VeryStrong). At least one patient with this variant displayed nemaline rods, which is highly specific for nemaline myopathy (PP4, PMID:17525139). A typical NM mouse model with compound heterozygous variants (p.Ser6366Ile and NebΔExon55) mimics features found in NM patients such as growth-retardation, muscle weakness, and atrophic muscles that contain nemaline rods and structural features consistent with NM. The S6366I-Homozygous model has a phenotype that develops with age and appears to share similarities with Finnish distal myopathy patients (PMID:32483185)(PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PS3, PP3, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1907773/MONDO:0018958/146

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 6.91

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 Pathogenic. Variant got 8 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.19097G>T	p.Ser6366Ile	missense_variant	122/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.19097G>T	p.Ser6366Ile	missense_variant	122/182	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.19097G>T	p.Ser6366Ile	missense_variant	122/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.19097G>T	p.Ser6366Ile	missense_variant	122/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000589

AC:

AN:

237566

Hom.:

AF XY:

0.0000312

AC XY:

AN XY:

128396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000622

Gnomad NFE exome

AF:

0.00000936

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000214

AC:

AN:

1451264

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

721350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000510

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000249

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 03, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 14, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NEB function (PMID: 25110572). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 496132). This variant is also known as g.171944G>T; p.Ser4665Ile. This missense change has been observed in individual(s) with nemaline myopathy (PMID: 15336686, 16917880, 17525139). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Finnish ancestry (PMID: 16917880, 17525139, 25110572). This variant is present in population databases (rs191579691, gnomAD 0.06%). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 6366 of the NEB protein (p.Ser6366Ile). -

Nemaline myopathy

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	Aug 07, 2024	The c.19097G>T (p.Ser6366Ile) variant in NEB is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 6366. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004723 (30/63518 alleles) in the European (Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1. However, this variant is excluded from the application of BA1/BS1 by the ClinGen Congenital Myopathies VCEP as it is a well established pathogenic variant. The computational predictor REVEL gives a score of 0.829, which is above the threshold of 0.7, evidence that correlates with impact to NEB function (PP3). This variant has been detected in 10 individuals with nemaline myopathy. Eight of those individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 2 of those were confirmed in trans by family testing. Two individuals were homozygous for the variant (PMIDs: 25205138, 15336686, 17525139) (PM3_VeryStrong). At least one patient with this variant displayed nemaline rods, which is highly specific for nemaline myopathy (PP4, PMID: 17525139). A typical NM mouse model with compound heterozygous variants (p.Ser6366Ile and NebΔExon55) mimics features found in NM patients such as growth-retardation, muscle weakness, and atrophic muscles that contain nemaline rods and structural features consistent with NM. The S6366I-Homozygous model has a phenotype that develops with age and appears to share similarities with Finnish distal myopathy patients (PMID: 32483185)(PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PS3, PP3, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2017	Variant summary: The NEB c.19097G>T (p.Ser6366Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 7/78722 control chromosomes at a frequency of 0.0000889, which does not exceed the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355). The variant was reported in multiple patients affected with NM when in the compound heterozygous state with another pathogenic mutation. Additionally, a report of patients homozygous for the mutation describe two patients without classic NM but with a novel type of recessively inherited distal myopathy. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

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

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.68

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

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.61

MVP

0.96

MPC

0.37

ClinPred

0.95

GERP RS

5.5

Varity_R

0.62

gMVP

0.74

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