Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001164507.2(NEB):c.16269C>T(p.Ala5423Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00034 ( 1 hom., cov: 12)

Exomes 𝑓: 0.0014 ( 13 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0150

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, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-151581498-G-A is Benign according to our data. Variant chr2-151581498-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.015 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000337 (33/97878) while in subpopulation SAS AF = 0.00826 (18/2178). AF 95% confidence interval is 0.00534. There are 1 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 12. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AD,AR gene

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.16269C>T	p.Ala5423Ala	synonymous	Exon 103 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.16269C>T	p.Ala5423Ala	synonymous	Exon 103 of 182	NP_001157980.2
NEB	NM_001271208.2		c.16269C>T	p.Ala5423Ala	synonymous	Exon 103 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.16269C>T	p.Ala5423Ala	synonymous	Exon 103 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16269C>T	p.Ala5423Ala	synonymous	Exon 103 of 182	ENSP00000416578.2
NEB	ENST00000413693.5	TSL:5	c.459C>T	p.Ala153Ala	synonymous	Exon 3 of 74	ENSP00000410961.1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

97780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000827

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000121

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000948

Gnomad SAS

AF:

0.00875

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000159

Gnomad OTH

AF:

0.000882

GnomAD2 exomes

AF:

0.00224

AC:

277

AN:

123706

AF XY:

0.00283

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000664

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000148

Gnomad OTH exome

AF:

0.000292

GnomAD4 exome

AF:

0.00137

AC:

1182

AN:

863650

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

839

AN XY:

442212

show subpopulations

African (AFR)

AF:

0.000393

AC:

AN:

20334

American (AMR)

AF:

0.0000315

AC:

AN:

31776

Ashkenazi Jewish (ASJ)

AF:

0.0000483

AC:

AN:

20692

East Asian (EAS)

AF:

0.000572

AC:

AN:

31468

South Asian (SAS)

AF:

0.0160

AC:

1003

AN:

62504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46742

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

2888

European-Non Finnish (NFE)

AF:

0.000161

AC:

AN:

608034

Other (OTH)

AF:

0.00125

AC:

AN:

39212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

137

182

228

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:

0.000337

AC:

AN:

97878

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

45632

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

24266

American (AMR)

AF:

0.000121

AC:

AN:

8280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2702

East Asian (EAS)

AF:

0.000952

AC:

AN:

3152

South Asian (SAS)

AF:

0.00826

AC:

AN:

2178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000159

AC:

AN:

50338

Other (OTH)

AF:

0.00

AC:

AN:

1156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000701

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.2

(source)

DANN

Benign

0.20

PhyloP100

-0.015

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs542916866

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over