Genetic Variant NM_001164507.2:c.771T>C (chr2-151717467-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001164507.2(NEB):c.771T>C(p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,613,292 control chromosomes in the GnomAD database, including 514,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 38781 hom., cov: 32)

Exomes 𝑓: 0.80 ( 475844 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.311

Publications

21 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=-0.75).

BP6

Variant 2-151717467-A-G is Benign according to our data. Variant chr2-151717467-A-G is described in ClinVar as Benign. ClinVar VariationId is 95136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.311 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

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.771T>C	p.Ala257Ala	synonymous	Exon 10 of 182	NP_001157979.2	P20929-3
NEB	NM_001164508.2	MANE Select	c.771T>C	p.Ala257Ala	synonymous	Exon 10 of 182	NP_001157980.2	P20929-2
NEB	NM_001271208.2		c.771T>C	p.Ala257Ala	synonymous	Exon 10 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.771T>C	p.Ala257Ala	synonymous	Exon 10 of 182	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.771T>C	p.Ala257Ala	synonymous	Exon 10 of 182	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5	TSL:5	c.771T>C	p.Ala257Ala	synonymous	Exon 10 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.681

AC:

103529

AN:

152040

Hom.:

38775

Cov.:

show subpopulations

Gnomad AFR

AF:

0.357

Gnomad AMI

AF:

0.842

Gnomad AMR

AF:

0.811

Gnomad ASJ

AF:

0.727

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.860

Gnomad MID

AF:

0.763

Gnomad NFE

AF:

0.834

Gnomad OTH

AF:

0.724

GnomAD2 exomes

AF:

0.755

AC:

188045

AN:

249044

AF XY:

0.757

show subpopulations

Gnomad AFR exome

AF:

0.339

Gnomad AMR exome

AF:

0.863

Gnomad ASJ exome

AF:

0.737

Gnomad EAS exome

AF:

0.475

Gnomad FIN exome

AF:

0.852

Gnomad NFE exome

AF:

0.835

Gnomad OTH exome

AF:

0.788

GnomAD4 exome

AF:

0.799

AC:

1167823

AN:

1461134

Hom.:

475844

Cov.:

AF XY:

0.796

AC XY:

578963

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.345

AC:

11551

AN:

33468

American (AMR)

AF:

0.856

AC:

38254

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.739

AC:

19301

AN:

26130

East Asian (EAS)

AF:

0.439

AC:

17432

AN:

39684

South Asian (SAS)

AF:

0.655

AC:

56514

AN:

86228

European-Finnish (FIN)

AF:

0.850

AC:

45397

AN:

53388

Middle Eastern (MID)

AF:

0.773

AC:

4461

AN:

5768

European-Non Finnish (NFE)

AF:

0.836

AC:

929031

AN:

1111408

Other (OTH)

AF:

0.760

AC:

45882

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

10983

21966

32950

43933

54916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20812

41624

62436

83248

104060

<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:

0.681

AC:

103547

AN:

152158

Hom.:

38781

Cov.:

AF XY:

0.684

AC XY:

50863

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.356

AC:

14784

AN:

41470

American (AMR)

AF:

0.811

AC:

12411

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.727

AC:

2524

AN:

3472

East Asian (EAS)

AF:

0.458

AC:

2372

AN:

5178

South Asian (SAS)

AF:

0.650

AC:

3139

AN:

4828

European-Finnish (FIN)

AF:

0.860

AC:

9105

AN:

10586

Middle Eastern (MID)

AF:

0.765

AC:

225

AN:

294

European-Non Finnish (NFE)

AF:

0.834

AC:

56707

AN:

68010

Other (OTH)

AF:

0.716

AC:

1512

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1339

2678

4018

5357

6696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

786

1572

2358

3144

3930

<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:

0.783

Hom.:

83053

Bravo

AF:

0.665

Asia WGS

AF:

0.498

AC:

1736

AN:

3478

EpiCase

AF:

0.839

EpiControl

AF:

0.834

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 (5)

not provided (3)

Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.33

(source)

DANN

Benign

0.54

PhyloP100

-0.31

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