1-92102564-C-G

Variant names:

• chr1-92102564-C-G
• NM_001376131.1:c.439C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001376131.1(BTBD8):​c.439C>G​(p.Leu147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L147P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTBD8 NM_001376131.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.640
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06267813).

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.439C>G	p.Leu147Val	missense	Exon 3 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.439C>G	p.Leu147Val	missense	Exon 3 of 18	ENSP00000490161.1	Q5XKL5-3
	BTBD8	ENST00000342818.4	TSL:1	c.439C>G	p.Leu147Val	missense	Exon 3 of 9	ENSP00000343686.3	A0A8V8N7F1
	BTBD8	ENST00000370382.7	TSL:1	n.706C>G		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.91
DANN	Benign	0.38
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.64
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.026
Sift	Benign	0.87	T
Sift4G	Benign	0.55	T
Polyphen		0.061	B
Vest4		0.067
MutPred		0.45		Loss of catalytic residue at L147 (P = 0.025)
MVP		0.64
MPC		0.24
ClinPred		0.040	T
GERP RS		-0.034
Varity_R		0.046
Mutation Taster		=100/0	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

hg19: chr1-92568121;