chr2-241559650-C-T

Variant names:

• chr2-241559650-C-T
• rs2066495816
• NM_032515.5:c.167C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032515.5(BOK):​c.167C>T​(p.Ala56Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000807 in 1,239,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: BOK NM_032515.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

Genes affected

BOK (HGNC:1087): (BCL2 family apoptosis regulator BOK) The protein encoded by this gene belongs to the BCL2 family, members of which form homo- or heterodimers, and act as anti- or proapoptotic regulators that are involved in a wide variety of cellular processes. Studies in rat show that this protein has restricted expression in reproductive tissues, interacts strongly with some antiapoptotic BCL2 proteins, not at all with proapoptotic BCL2 proteins, and induces apoptosis in transfected cells. Thus, this protein represents a proapoptotic member of the BCL2 family. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09409961).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032515.5. 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
	BOK	NM_032515.5	MANE Select	c.167C>T	p.Ala56Val	missense	Exon 2 of 5	NP_115904.1	A0A024R4A8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BOK	ENST00000318407.5	TSL:1 MANE Select	c.167C>T	p.Ala56Val	missense	Exon 2 of 5	ENSP00000314132.3	Q9UMX3-1
	BOK	ENST00000853586.1		c.167C>T	p.Ala56Val	missense	Exon 1 of 5	ENSP00000523645.1
	BOK	ENST00000969136.1		c.167C>T	p.Ala56Val	missense	Exon 2 of 6	ENSP00000639195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.07e-7 AC: 1 AN: 1239404 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 606392

⚠️ 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: 24388

American (AMR) AF: 0.00 AC: 0 AN: 12976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18068

East Asian (EAS) AF: 0.00 AC: 0 AN: 27822

South Asian (SAS) AF: 0.00 AC: 0 AN: 56936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4540

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1013518

Other (OTH) AF: 0.00 AC: 0 AN: 50936

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.040	N
REVEL	Benign	0.012
Sift	Benign	0.36	T
Sift4G	Benign	0.41	T
Polyphen		0.040	B
Vest4		0.14
MutPred		0.29		Loss of disorder (P = 0.0662)
MVP		0.22
MPC		1.3
ClinPred		0.067	T
GERP RS		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.063
gMVP		0.27
Mutation Taster		=98/2	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: rs2066495816; hg19: chr2-242499065;