rs2946642

Variant names:

• chr15-65077193-G-T
• rs2946642
• NM_001101362.3:c.378G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001101362.3(KBTBD13):​c.378G>T​(p.Ala126Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,481,882 control chromosomes in the GnomAD database, including 123,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16011 hom., cov: 34)
  • Exomes 𝑓: 0.40 (107422 hom.)
• Consequence: KBTBD13 NM_001101362.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.272
• Publications: 13 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-65077193-G-T is Benign according to our data. Variant chr15-65077193-G-T is described in ClinVar as Benign. ClinVar VariationId is 129309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.272 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

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.378G>T	p.Ala126Ala	synonymous	Exon 1 of 1	NP_001094832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	ENST00000432196.5	TSL:6 MANE Select	c.378G>T	p.Ala126Ala	synonymous	Exon 1 of 1	ENSP00000388723.2

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68187 AN: 151734 Hom.: 15983 Cov.: 34

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.427

GnomAD2 exomes AF: 0.467 AC: 44457 AN: 95214 AF XY: 0.449

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.766

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.397 AC: 527645 AN: 1330040 Hom.: 107422 Cov.: 52 AF XY: 0.395 AC XY: 257983 AN XY: 653144

African (AFR) AF: 0.563 AC: 15306 AN: 27198

American (AMR) AF: 0.550 AC: 16118 AN: 29288

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 8075 AN: 23234

East Asian (EAS) AF: 0.738 AC: 23598 AN: 31958

South Asian (SAS) AF: 0.343 AC: 25172 AN: 73304

European-Finnish (FIN) AF: 0.395 AC: 13111 AN: 33208

Middle Eastern (MID) AF: 0.373 AC: 1981 AN: 5316

European-Non Finnish (NFE) AF: 0.382 AC: 401540 AN: 1051424

Other (OTH) AF: 0.413 AC: 22744 AN: 55110

GnomAD4 genome AF: 0.450 AC: 68258 AN: 151842 Hom.: 16011 Cov.: 34 AF XY: 0.451 AC XY: 33453 AN XY: 74222

African (AFR) AF: 0.552 AC: 22888 AN: 41466

American (AMR) AF: 0.477 AC: 7268 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1126 AN: 3464

East Asian (EAS) AF: 0.711 AC: 3664 AN: 5150

South Asian (SAS) AF: 0.333 AC: 1609 AN: 4830

European-Finnish (FIN) AF: 0.403 AC: 4228 AN: 10496

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.384 AC: 26088 AN: 67876

Other (OTH) AF: 0.431 AC: 909 AN: 2110

Alfa AF: 0.407 Hom.: 2472

Bravo AF: 0.467

Asia WGS AF: 0.496 AC: 1697 AN: 3430

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Nemaline myopathy 6 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.2
DANN	Benign	0.79
PhyloP100		-0.27
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2946642; hg19: chr15-65369531; COSMIC: COSV71351671; COSMIC: COSV71351671;