NM_001164507.2:c.12808C>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001164507.2(NEB):c.12808C>A(p.Gln4270Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 7)

Exomes 𝑓: 0.000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -3.60

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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11250013).

BP6

Variant 2-151604811-G-T is Benign according to our data. Variant chr2-151604811-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392823.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12808C>A	p.Gln4270Lys	missense_variant	Exon 85 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12808C>A	p.Gln4270Lys	missense_variant	Exon 85 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.12808C>A	p.Gln4270Lys	missense_variant	Exon 85 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.12808C>A	p.Gln4270Lys	missense_variant	Exon 85 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+4998C>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000191

AC:

AN:

52294

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000482

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000173

AC:

AN:

462928

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

AN XY:

243476

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

11200

American (AMR)

AF:

0.00

AC:

AN:

18436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12980

East Asian (EAS)

AF:

0.00

AC:

AN:

25130

South Asian (SAS)

AF:

0.00

AC:

AN:

44288

European-Finnish (FIN)

AF:

0.0000395

AC:

AN:

25348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1814

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

299038

Other (OTH)

AF:

0.00

AC:

AN:

24694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.237

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:1

Dec 04, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 12, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.68

CADD

Benign

3.3

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.014

.;T;.;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.70

T;T;T;.;.

M_CAP

Benign

0.0041

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

-3.6

PROVEAN

Benign

-0.88

N;.;N;.;.

REVEL

Benign

0.038

Sift

Benign

0.61

T;.;T;.;.

Sift4G

Benign

0.092

T;T;T;T;T

Vest4

0.19

MutPred

0.49

Gain of ubiquitination at Q4270 (P = 0.0238);Gain of ubiquitination at Q4270 (P = 0.0238);Gain of ubiquitination at Q4270 (P = 0.0238);Gain of ubiquitination at Q4270 (P = 0.0238);Gain of ubiquitination at Q4270 (P = 0.0238);

MVP

0.20

MPC

0.14

ClinPred

0.022

GERP RS

1.0

gMVP

0.00074

Mutation Taster

=89/11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over