15-65077148-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001101362.3(KBTBD13):c.333C>G(p.Asp111Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,513,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D111N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

KBTBD13
NM_001101362.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.130

Publications

1 publications found

Variant links:

Genes affected

KBTBD13 (HGNC:37227): (kelch repeat and BTB domain containing 13) The gene belongs to a family of genes encoding proteins containing a BTB domain and several kelch repeats. The BTB domain functions as a protein-protein interaction module, which includes an ability to self-associate or to interact with non-BTB domain-containing proteins. The kelch motif typically occurs in groups of five to seven repeats, and has been found in proteins with diverse functions. Known functions of these family members include transcription regulation, ion channel tetramerization and gating, protein ubiquitination or degradation, and cytoskeleton regulation. The exact function of this family member has yet to be determined. [provided by RefSeq, Jun 2010]

KBTBD13 Gene-Disease associations (from GenCC):

nemaline myopathy 6
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KBTBD13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056417286).

BP6

Variant 15-65077148-C-G is Benign according to our data. Variant chr15-65077148-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 316739.

BS2

High AC in GnomAd4 at 146 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101362.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	NM_001101362.3	MANE Select	c.333C>G	p.Asp111Glu	missense	Exon 1 of 1	NP_001094832.1	C9JR72

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	ENST00000432196.5	TSL:6 MANE Select	c.333C>G	p.Asp111Glu	missense	Exon 1 of 1	ENSP00000388723.2	C9JR72

Frequencies

GnomAD3 genomes

AF:

0.000941

AC:

143

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000221

AC:

AN:

113304

AF XY:

0.000223

show subpopulations

Gnomad AFR exome

AF:

0.00463

Gnomad AMR exome

AF:

0.000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000468

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

140

AN:

1361788

Hom.:

Cov.:

AF XY:

0.0000893

AC XY:

AN XY:

671818

show subpopulations

African (AFR)

AF:

0.00304

AC:

AN:

28606

American (AMR)

AF:

0.000359

AC:

AN:

33442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24300

East Asian (EAS)

AF:

0.00

AC:

AN:

33698

South Asian (SAS)

AF:

0.0000260

AC:

AN:

76970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34314

Middle Eastern (MID)

AF:

0.000362

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1068256

Other (OTH)

AF:

0.000194

AC:

AN:

56674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000960

AC:

146

AN:

152066

Hom.:

Cov.:

AF XY:

0.000874

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00337

AC:

140

AN:

41494

American (AMR)

AF:

0.000262

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000436

Hom.:

Bravo

AF:

0.00110

ExAC

AF:

0.0000449

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 6 (2)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.0081

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

PhyloP100

-0.13

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.14

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0070

Vest4

0.096

MutPred

0.52

Gain of helix (P = 0.0325)

MVP

0.39

MPC

0.50

ClinPred

0.0047

GERP RS

-2.7

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.074

gMVP

0.22

Mutation Taster

=94/6

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

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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