dbSNP rs373946448: NEB:p.Ala761Ala (chr2-151690754-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001164508.2(NEB):c.2283C>T(p.Ala761Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,597,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene NEB is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.454

Publications

0 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, Myriad Women's Health, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
autosomal dominant nebulin-related myopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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

new If you want to explore the variant's impact on the transcript NM_001164508.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-151690754-G-A is Benign according to our data. Variant chr2-151690754-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195822.

BP7

Synonymous conserved (PhyloP=0.454 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (150/152236) while in subpopulation AFR AF = 0.0034 (141/41528). AF 95% confidence interval is 0.00294. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEB	NM_001164507.2	MANE Plus Clinical	c.2283C>T	p.Ala761Ala	synonymous	Exon 24 of 182	NP_001157979.2	P20929-3
NEB	NM_001164508.2	MANE Select	c.2283C>T	p.Ala761Ala	synonymous	Exon 24 of 182	NP_001157980.2	P20929-2
NEB	NM_001271208.2		c.2283C>T	p.Ala761Ala	synonymous	Exon 24 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEB	ENST00000397345.8	TSL:5 MANE Select	c.2283C>T	p.Ala761Ala	synonymous	Exon 24 of 182	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.2283C>T	p.Ala761Ala	synonymous	Exon 24 of 182	ENSP00000416578.2	P20929-3
NEB	ENST00000489048.1	TSL:1	n.1182C>T		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

AF:

0.000986

AC:

150

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000226

AC:

AN:

225518

AF XY:

0.000190

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0000627

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000989

AC:

143

AN:

1445188

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

716744

show subpopulations

African (AFR)

AF:

0.00367

AC:

122

AN:

33284

American (AMR)

AF:

0.0000707

AC:

AN:

42430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

39266

South Asian (SAS)

AF:

0.00

AC:

AN:

82746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52482

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103570

Other (OTH)

AF:

0.000284

AC:

AN:

59870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152236

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00340

AC:

141

AN:

41528

American (AMR)

AF:

0.000327

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

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:

0.000665

Hom.:

Bravo

AF:

0.00110

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 2 (2)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

4.7

(source)

DANN

Benign

0.63

PhyloP100

0.45

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over