dbSNP rs61730771: NEB:p.His2822His (chr2-151640574-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_001164508.2(NEB):c.8466C>T(p.His2822His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,806 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 63 hom., cov: 32)

Exomes 𝑓: 0.019 ( 395 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.48

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 2-151640574-G-A is Benign according to our data. Variant chr2-151640574-G-A is described in ClinVar as Benign. ClinVar VariationId is 129759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.48 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0247 (3755/152116) while in subpopulation SAS AF = 0.0455 (219/4816). AF 95% confidence interval is 0.0405. There are 63 homozygotes in GnomAd4. There are 1832 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 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	HGVSp	Effect	Exon Rank	Protein	UniProt
NEB	NM_001164507.2	MANE Plus Clinical	c.8466C>T	p.His2822His	synonymous	Exon 61 of 182	NP_001157979.2	P20929-3
NEB	NM_001164508.2	MANE Select	c.8466C>T	p.His2822His	synonymous	Exon 61 of 182	NP_001157980.2	P20929-2
NEB	NM_001271208.2		c.8466C>T	p.His2822His	synonymous	Exon 61 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.8466C>T	p.His2822His	synonymous	Exon 61 of 182	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.8466C>T	p.His2822His	synonymous	Exon 61 of 182	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5	TSL:5	c.8466C>T	p.His2822His	synonymous	Exon 61 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3744

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0415

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.00444

Gnomad SAS

AF:

0.0446

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0273

GnomAD2 exomes

AF:

0.0211

AC:

5256

AN:

249214

AF XY:

0.0223

show subpopulations

Gnomad AFR exome

AF:

0.0462

Gnomad AMR exome

AF:

0.00857

Gnomad ASJ exome

AF:

0.0467

Gnomad EAS exome

AF:

0.00406

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0192

AC:

27994

AN:

1461690

Hom.:

395

Cov.:

AF XY:

0.0200

AC XY:

14566

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.0456

AC:

1527

AN:

33480

American (AMR)

AF:

0.00953

AC:

426

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0468

AC:

1224

AN:

26134

East Asian (EAS)

AF:

0.00186

AC:

AN:

39700

South Asian (SAS)

AF:

0.0473

AC:

4084

AN:

86258

European-Finnish (FIN)

AF:

0.0124

AC:

663

AN:

53402

Middle Eastern (MID)

AF:

0.0290

AC:

167

AN:

5768

European-Non Finnish (NFE)

AF:

0.0165

AC:

18361

AN:

1111850

Other (OTH)

AF:

0.0243

AC:

1468

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

1735

3470

5204

6939

8674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.0247

AC:

3755

AN:

152116

Hom.:

Cov.:

AF XY:

0.0246

AC XY:

1832

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0415

AC:

1724

AN:

41508

American (AMR)

AF:

0.0158

AC:

241

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

148

AN:

3468

East Asian (EAS)

AF:

0.00445

AC:

AN:

5164

South Asian (SAS)

AF:

0.0455

AC:

219

AN:

4816

European-Finnish (FIN)

AF:

0.0123

AC:

130

AN:

10580

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1178

AN:

67986

Other (OTH)

AF:

0.0270

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

186

373

559

746

932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0181

Hom.:

Bravo

AF:

0.0250

Asia WGS

AF:

0.0410

AC:

142

AN:

3478

EpiCase

AF:

0.0178

EpiControl

AF:

0.0200

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Nemaline myopathy 2 (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.68

(source)

DANN

Benign

0.50

PhyloP100

-2.5

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