1-92088726-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001376131.1(BTBD8):​c.178G>A​(p.Val60Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,610,170 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 𝑓 0.019 (40 hom., cov: 32)
  • Exomes 𝑓: 0.025 (569 hom.)
• Consequence: BTBD8 NM_001376131.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 29 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005039811).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0193 (2935/152124) while in subpopulation NFE AF = 0.028 (1900/67974). AF 95% confidence interval is 0.0269. There are 40 homozygotes in GnomAd4. There are 1432 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

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>A	p.Val60Ile	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>A	p.Val60Ile	missense	Exon 2 of 18	ENSP00000490161.1	Q5XKL5-3
	BTBD8	ENST00000342818.4	TSL:1	c.178G>A	p.Val60Ile	missense	Exon 2 of 9	ENSP00000343686.3	A0A8V8N7F1
	BTBD8	ENST00000370382.7	TSL:1	n.445G>A		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2936 AN: 152006 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00498

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0202 AC: 5071 AN: 250480 AF XY: 0.0200

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0252 AC: 36719 AN: 1458046 Hom.: 569 Cov.: 31 AF XY: 0.0243 AC XY: 17618 AN XY: 725354

African (AFR) AF: 0.00413 AC: 138 AN: 33402

American (AMR) AF: 0.0109 AC: 485 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 62 AN: 26020

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39496

South Asian (SAS) AF: 0.00588 AC: 503 AN: 85600

European-Finnish (FIN) AF: 0.0357 AC: 1901 AN: 53214

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5752

European-Non Finnish (NFE) AF: 0.0292 AC: 32439 AN: 1109906

Other (OTH) AF: 0.0196 AC: 1181 AN: 60182

GnomAD4 genome AF: 0.0193 AC: 2935 AN: 152124 Hom.: 40 Cov.: 32 AF XY: 0.0193 AC XY: 1432 AN XY: 74344

African (AFR) AF: 0.00496 AC: 206 AN: 41512

American (AMR) AF: 0.0189 AC: 289 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4812

European-Finnish (FIN) AF: 0.0439 AC: 464 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0280 AC: 1900 AN: 67974

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

Alfa AF: 0.0244 Hom.: 174

Bravo AF: 0.0172

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0302 AC: 260

ExAC AF: 0.0221 AC: 2684

Asia WGS AF: 0.00347 AC: 12 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.070
Sift	Benign	0.12	T
Sift4G	Benign	0.30	T
Polyphen		0.12	B
Vest4		0.12
MPC		0.19
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.045
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: rs34856868; hg19: chr1-92554283;