15-65077061-G-C

Variant names:

• chr15-65077061-G-C
• rs115182478
• NM_001101362.3:c.246G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001101362.3(KBTBD13):​c.246G>C​(p.Val82Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,512,498 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 34)
  • Exomes 𝑓: 0.00089 (15 hom.)
• Consequence: KBTBD13 NM_001101362.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.318
• Publications: 1 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=-0.5).
• BP6: Variant 15-65077061-G-C is Benign according to our data. Variant chr15-65077061-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.318 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00679 (1034/152182) while in subpopulation AFR AF = 0.0229 (953/41560). AF 95% confidence interval is 0.0217. There are 12 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1034 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.246G>C	p.Val82Val	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.246G>C	p.Val82Val	synonymous	Exon 1 of 1	ENSP00000388723.2

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 1028 AN: 152074 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00121 AC: 140 AN: 115890 AF XY: 0.00109

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000885 AC: 1204 AN: 1360316 Hom.: 15 Cov.: 58 AF XY: 0.000857 AC XY: 575 AN XY: 671112

African (AFR) AF: 0.0239 AC: 694 AN: 29094

American (AMR) AF: 0.00258 AC: 85 AN: 32920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24284

East Asian (EAS) AF: 0.00 AC: 0 AN: 34238

South Asian (SAS) AF: 0.000353 AC: 27 AN: 76544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36410

Middle Eastern (MID) AF: 0.00369 AC: 20 AN: 5424

European-Non Finnish (NFE) AF: 0.000205 AC: 218 AN: 1064802

Other (OTH) AF: 0.00283 AC: 160 AN: 56600

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152182 Hom.: 12 Cov.: 34 AF XY: 0.00656 AC XY: 488 AN XY: 74418

African (AFR) AF: 0.0229 AC: 953 AN: 41560

American (AMR) AF: 0.00249 AC: 38 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67964

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.000723 Hom.: 0

Asia WGS AF: 0.00261 AC: 9 AN: 3458

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nemaline myopathy 6 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.0
DANN	Benign	0.83
PhyloP100		-0.32
PromoterAI		0.0030	Neutral
Mutation Taster		=99/1	polymorphism

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: rs115182478; hg19: chr15-65369399;