Genetic Variant NM_001164507.2:c.8318G>A (chr2-151642629-C-T) – 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_001164507.2(NEB):c.8318G>A(p.Arg2773Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0257 in 1,613,648 control chromosomes in the GnomAD database, including 644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2773W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 51 hom., cov: 33)

Exomes 𝑓: 0.026 ( 593 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.95

Publications

17 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 (MetaRNN=0.0036732256).

BP6

Variant 2-151642629-C-T is Benign according to our data. Variant chr2-151642629-C-T is described in ClinVar as Benign. ClinVar VariationId is 129758.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 = 0.0188 (2869/152280) while in subpopulation SAS AF = 0.0453 (219/4830). AF 95% confidence interval is 0.0404. There are 51 homozygotes in GnomAd4. There are 1393 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 51 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	UniProt
NEB	NM_001164507.2	MANE Plus Clinical	c.8318G>A	p.Arg2773Gln	missense	Exon 60 of 182	NP_001157979.2	P20929-3
NEB	NM_001164508.2	MANE Select	c.8318G>A	p.Arg2773Gln	missense	Exon 60 of 182	NP_001157980.2	P20929-2
NEB	NM_001271208.2		c.8318G>A	p.Arg2773Gln	missense	Exon 60 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.8318G>A	p.Arg2773Gln	missense	Exon 60 of 182	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.8318G>A	p.Arg2773Gln	missense	Exon 60 of 182	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5	TSL:5	c.8318G>A	p.Arg2773Gln	missense	Exon 60 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2865

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00500

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0458

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0261

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0236

AC:

5875

AN:

248938

AF XY:

0.0252

show subpopulations

Gnomad AFR exome

AF:

0.00497

Gnomad AMR exome

AF:

0.00791

Gnomad ASJ exome

AF:

0.0494

Gnomad EAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0264

AC:

38538

AN:

1461368

Hom.:

593

Cov.:

AF XY:

0.0271

AC XY:

19710

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.00412

AC:

138

AN:

33478

American (AMR)

AF:

0.00863

AC:

386

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

1304

AN:

26120

East Asian (EAS)

AF:

0.00771

AC:

306

AN:

39680

South Asian (SAS)

AF:

0.0478

AC:

4119

AN:

86188

European-Finnish (FIN)

AF:

0.0155

AC:

830

AN:

53378

Middle Eastern (MID)

AF:

0.0227

AC:

131

AN:

5762

European-Non Finnish (NFE)

AF:

0.0267

AC:

29653

AN:

1111672

Other (OTH)

AF:

0.0277

AC:

1671

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1897

3794

5690

7587

9484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1172

2344

3516

4688

5860

<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:

0.0188

AC:

2869

AN:

152280

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

1393

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00498

AC:

207

AN:

41556

American (AMR)

AF:

0.0143

AC:

218

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

159

AN:

3472

East Asian (EAS)

AF:

0.0108

AC:

AN:

5188

South Asian (SAS)

AF:

0.0453

AC:

219

AN:

4830

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0261

AC:

1774

AN:

68020

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

150

301

451

602

752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0242

Hom.:

165

Bravo

AF:

0.0170

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00558

AC:

ESP6500EA

AF:

0.0285

AC:

234

ExAC

AF:

0.0235

AC:

2837

Asia WGS

AF:

0.0380

AC:

132

AN:

3478

EpiCase

AF:

0.0257

EpiControl

AF:

0.0278

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Nemaline myopathy 2 (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.7

PhyloP100

4.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Benign

0.14

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.70

MPC

0.36

ClinPred

0.099

GERP RS

6.2

Varity_R

0.22

gMVP

0.28

Mutation Taster

=99/1

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

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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