NM_001164507.2:c.3826C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001164507.2(NEB):c.3826C>A(p.Pro1276Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,594,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1276R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.35

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

nemaline myopathy 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010675073).

BP6

Variant 2-151675340-G-T is Benign according to our data. Variant chr2-151675340-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00308 (469/152292) while in subpopulation AFR AF = 0.01 (416/41570). AF 95% confidence interval is 0.00921. There are 1 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.3826C>A	p.Pro1276Thr	missense_variant	Exon 35 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.3826C>A	p.Pro1276Thr	missense_variant	Exon 35 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.3826C>A	p.Pro1276Thr	missense_variant	Exon 35 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.3826C>A	p.Pro1276Thr	missense_variant	Exon 35 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.3826C>A	p.Pro1276Thr	missense_variant	Exon 35 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

466

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00999

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.000824

AC:

182

AN:

220918

AF XY:

0.000582

show subpopulations

Gnomad AFR exome

AF:

0.00906

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000720

Gnomad OTH exome

AF:

0.000542

GnomAD4 exome

AF:

0.000438

AC:

632

AN:

1442410

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

297

AN XY:

715494

show subpopulations

African (AFR)

AF:

0.0115

AC:

382

AN:

33238

American (AMR)

AF:

0.00168

AC:

AN:

42208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

39330

South Asian (SAS)

AF:

0.0000966

AC:

AN:

82856

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52544

Middle Eastern (MID)

AF:

0.00209

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000863

AC:

AN:

1101068

Other (OTH)

AF:

0.00106

AC:

AN:

59714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00308

AC:

469

AN:

152292

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0100

AC:

416

AN:

41570

American (AMR)

AF:

0.00235

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00370

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000904

AC:

109

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 17, 2020

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BP4

Nemaline myopathy 2

Benign:3

Nov 11, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

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

Eigen

Benign

-0.15

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

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

MetaRNN

Benign

0.011

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.;L;L;L;L

PhyloP100

2.3

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.1

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

REVEL

Benign

0.13

Sift

Uncertain

0.0060

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

Sift4G

Benign

0.11

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

Vest4

0.57

ClinPred

0.039

GERP RS

4.6

Varity_R

0.27

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over