dbSNP rs117178114: NEB:p.Asp4Asp (chr2-151733145-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6BP7BS1BS2_Supporting

The NM_001164507.2(NEB):c.12C>T(p.Asp4Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,603,876 control chromosomes in the GnomAD database, including 3 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 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00075 ( 2 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.404

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 2-151733145-G-A is Benign according to our data. Variant chr2-151733145-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95107.

BP7

Synonymous conserved (PhyloP=-0.404 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00112 (169/151524) while in subpopulation EAS AF = 0.00969 (50/5162). AF 95% confidence interval is 0.00755. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	NM_001164507.2	MANE Plus Clinical	c.12C>T	p.Asp4Asp	synonymous	Exon 3 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.12C>T	p.Asp4Asp	synonymous	Exon 3 of 182	NP_001157980.2
NEB	NM_001271208.2		c.12C>T	p.Asp4Asp	synonymous	Exon 3 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.12C>T	p.Asp4Asp	synonymous	Exon 3 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12C>T	p.Asp4Asp	synonymous	Exon 3 of 182	ENSP00000416578.2
NEB	ENST00000409198.5	TSL:5	c.12C>T	p.Asp4Asp	synonymous	Exon 3 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

169

AN:

151408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000461

Gnomad ASJ

AF:

0.00895

Gnomad EAS

AF:

0.00966

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.00142

AC:

337

AN:

236506

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.00787

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000253

Gnomad OTH exome

AF:

0.000870

GnomAD4 exome

AF:

0.000754

AC:

1095

AN:

1452352

Hom.:

Cov.:

AF XY:

0.000754

AC XY:

544

AN XY:

721694

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33322

American (AMR)

AF:

0.00127

AC:

AN:

43988

Ashkenazi Jewish (ASJ)

AF:

0.00698

AC:

181

AN:

25942

East Asian (EAS)

AF:

0.00807

AC:

319

AN:

39546

South Asian (SAS)

AF:

0.00128

AC:

108

AN:

84384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51548

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000278

AC:

308

AN:

1107870

Other (OTH)

AF:

0.00143

AC:

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00112

AC:

169

AN:

151524

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74004

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

41248

American (AMR)

AF:

0.000460

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00895

AC:

AN:

3464

East Asian (EAS)

AF:

0.00969

AC:

AN:

5162

South Asian (SAS)

AF:

0.00271

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67920

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00112

Hom.:

Bravo

AF:

0.00128

Asia WGS

AF:

0.00636

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BP4, BP7

Apr 13, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 20, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nemaline myopathy 2

Benign:3

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 24, 2020

Natera, Inc.

Significance:Likely 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.

not specified

Benign:2

May 03, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.0

(source)

DANN

Benign

0.57

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over