dbSNP rs78226234: NEB:c.7644+25T>C (chr2-151644443-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164508.2(NEB):c.7644+25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,569,952 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 32)

Exomes 𝑓: 0.018 ( 325 hom. )

Consequence

NEB
NM_001164508.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.733

Publications

1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-151644443-A-G is Benign according to our data. Variant chr2-151644443-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 257831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0122 (1861/152296) while in subpopulation SAS AF = 0.0317 (153/4824). AF 95% confidence interval is 0.0276. There are 18 homozygotes in GnomAd4. There are 876 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
NEB	NM_001164507.2	MANE Plus Clinical	c.7644+25T>C	intron	N/A	NP_001157979.2	P20929-3
NEB	NM_001164508.2	MANE Select	c.7644+25T>C	intron	N/A	NP_001157980.2	P20929-2
NEB	NM_001271208.2		c.7644+25T>C	intron	N/A	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEB	ENST00000397345.8	TSL:5 MANE Select	c.7644+25T>C	intron	N/A	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.7644+25T>C	intron	N/A	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5	TSL:5	c.7644+25T>C	intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1863

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00675

Gnomad SAS

AF:

0.0319

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0147

AC:

3655

AN:

247888

AF XY:

0.0159

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.00831

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00424

Gnomad FIN exome

AF:

0.00400

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0183

AC:

25969

AN:

1417656

Hom.:

325

Cov.:

AF XY:

0.0186

AC XY:

13157

AN XY:

707792

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

32448

American (AMR)

AF:

0.00868

AC:

386

AN:

44488

Ashkenazi Jewish (ASJ)

AF:

0.00305

AC:

AN:

25874

East Asian (EAS)

AF:

0.00449

AC:

177

AN:

39450

South Asian (SAS)

AF:

0.0336

AC:

2857

AN:

84972

European-Finnish (FIN)

AF:

0.00553

AC:

295

AN:

53374

Middle Eastern (MID)

AF:

0.00440

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0197

AC:

21152

AN:

1072488

Other (OTH)

AF:

0.0154

AC:

906

AN:

58878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1304

2609

3913

5218

6522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.0122

AC:

1861

AN:

152296

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

876

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41582

American (AMR)

AF:

0.0117

AC:

179

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.00677

AC:

AN:

5170

South Asian (SAS)

AF:

0.0317

AC:

153

AN:

4824

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1256

AN:

68016

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

198

296

395

494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0151

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance: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

-0.92

CADD

Benign

0.033

(source)

DANN

Benign

0.43

PhyloP100

-0.73

Mutation Taster

=100/0

polymorphism (auto)

(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.

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