15-65077059-G-A

Variant names:

• chr15-65077059-G-A
• rs1303411209
• NM_001101362.3:c.244G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5 BS2

The NM_001101362.3(KBTBD13):​c.244G>A​(p.Val82Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000441 in 1,359,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V82E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 4.95
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP5: Variant 15-65077059-G-A is Pathogenic according to our data. Variant chr15-65077059-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435545.
• BS2: High AC in GnomAdExome4 at 6 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.244G>A	p.Val82Met	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.244G>A	p.Val82Met	missense	Exon 1 of 1	ENSP00000388723.2	C9JR72

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000868 AC: 1 AN: 115224 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000441 AC: 6 AN: 1359662 Hom.: 0 Cov.: 58 AF XY: 0.00000298 AC XY: 2 AN XY: 670754

African (AFR) AF: 0.00 AC: 0 AN: 29080

American (AMR) AF: 0.00 AC: 0 AN: 32802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24216

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34226

South Asian (SAS) AF: 0.0000393 AC: 3 AN: 76404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1064526

Other (OTH) AF: 0.00 AC: 0 AN: 56568

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Nemaline myopathy 6 (2)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.43		Gain of catalytic residue at V82 (P = 0.0165)
MVP		0.69
MPC		1.5
ClinPred		0.77	D
GERP RS		3.7
PromoterAI		-0.028	Neutral
Varity_R		0.27
gMVP		0.52
Mutation Taster		=81/19	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1303411209; hg19: chr15-65369397;