1-92088726-G-C

Variant names:

• chr1-92088726-G-C
• rs34856868
• NM_001376131.1:c.178G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001376131.1(BTBD8):​c.178G>C​(p.Val60Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BTBD8 NM_001376131.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

BTBD8 (HGNC:21019): (BTB domain containing 8) Predicted to be involved in clathrin-dependent synaptic vesicle endocytosis; neuron projection development; and synaptic vesicle budding from endosome. Located in nucleoplasm. Colocalizes with AP-2 adaptor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376131.1. 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
	BTBD8	NM_001376131.1	MANE Select	c.178G>C	p.Val60Leu	missense	Exon 2 of 18	NP_001363060.1	Q5XKL5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTBD8	ENST00000636805.2	TSL:5 MANE Select	c.178G>C	p.Val60Leu	missense	Exon 2 of 18	ENSP00000490161.1	Q5XKL5-3
	BTBD8	ENST00000342818.4	TSL:1	c.178G>C	p.Val60Leu	missense	Exon 2 of 9	ENSP00000343686.3	A0A8V8N7F1
	BTBD8	ENST00000370382.7	TSL:1	n.445G>C		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458212 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725422

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110058

Other (OTH) AF: 0.00 AC: 0 AN: 60186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.0034
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.051	T
Polyphen		0.19	B
Vest4		0.49
MutPred		0.77		Loss of catalytic residue at S63 (P = 0.2946)
MVP		0.80
MPC		0.36
ClinPred		0.87	D
GERP RS		3.4
Varity_R		0.24
Mutation Taster		=98/2	polymorphism

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: rs34856868; hg19: chr1-92554283;