chr14-105249178-C-G

Variant names:

• chr14-105249178-C-G
• rs2816605
• NM_001387567.1:c.396C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001387567.1(BTBD6):​c.396C>G​(p.Asn132Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BTBD6 NM_001387567.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.653

Genes affected

BTBD6 (HGNC:19897): (BTB domain containing 6) Predicted to be involved in neurogenesis. Predicted to be located in cytoplasm. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

BRF1 (HGNC:11551): (BRF1 RNA polymerase III transcription initiation factor subunit) This gene encodes one of the three subunits of the RNA polymerase III transcription factor complex. This complex plays a central role in transcription initiation by RNA polymerase III on genes encoding tRNA, 5S rRNA, and other small structural RNAs. The gene product belongs to the TF2B family. Several alternatively spliced variants encoding different isoforms, that function at different promoters transcribed by RNA polymerase III, have been identified. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTBD6	NM_001387567.1	c.396C>G	p.Asn132Lys	missense_variant	Exon 2 of 4	ENST00000392554.8	NP_001374496.1
BRF1	NM_001519.4	c.544+3329G>C		intron_variant	Intron 5 of 17	ENST00000547530.7	NP_001510.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTBD6	ENST00000392554.8	c.396C>G	p.Asn132Lys	missense_variant	Exon 2 of 4	1	NM_001387567.1	ENSP00000376337.4
BRF1	ENST00000547530.7	c.544+3329G>C		intron_variant	Intron 5 of 17	1	NM_001519.4	ENSP00000448387.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431490 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 710976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.237C>G (p.N79K) alteration is located in exon 3 (coding exon 2) of the BTBD6 gene. This alteration results from a C to G substitution at nucleotide position 237, causing the asparagine (N) at amino acid position 79 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D;D;.;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L;.;L;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;T;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.53
MutPred		0.51		Gain of ubiquitination at N79 (P = 0.0185);Gain of ubiquitination at N79 (P = 0.0185);Gain of ubiquitination at N79 (P = 0.0185);.;.;
MVP		0.29
MPC		1.3
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.82
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2816605; hg19: chr14-105715515;