22-43129222-G-C

Variant names:

• chr22-43129222-G-C
• rs532663391
• NM_001197.5:c.400G>C
• BIK p.Glu134Gln

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_Strong

The NM_001197.5(BIK):c.400G>C (p.Glu134Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000399 (AC=64) in the gnomAD database across 1,604,714 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00134. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E134K: Uncertain_significance (ClinVar VariationId 2511868, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: BIK NM_001197.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 2 publications found

Genes affected

BIK (HGNC:1051): (BCL2 interacting killer) The protein encoded by this gene shares a critical BH3 domain with other death-promoting proteins, such as BID, BAK, BAD and BAX, that is required for its pro-apoptotic activity, and for interaction with anti-apoptotic members of the BCL2 family, and viral survival-promoting proteins. Since the activity of this protein is suppressed in the presence of survival-promoting proteins, it is suggested as a likely target for anti-apoptotic proteins. [provided by RefSeq, Sep 2011]

BIK Gene-Disease associations (from GenCC):

• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 64 (pure AD gene, not AR).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001197.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIK	NM_001197.5	MANE Select	c.400G>C	p.Glu134Gln	missense	Exon 5 of 5	NP_001188.1	Q13323

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIK	ENST00000216115.3	TSL:1 MANE Select	c.400G>C	p.Glu134Gln	missense	Exon 5 of 5	ENSP00000216115.2	Q13323
	BIK	ENST00000918052.1		c.514G>C	p.Glu172Gln	missense	Exon 6 of 6	ENSP00000588111.1	A0ACI8SWR1
	BIK	ENST00000910665.1		c.400G>C	p.Glu134Gln	missense	Exon 7 of 7	ENSP00000580724.1	Q13323

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000789	AC:12	Hom:0	AN:152044	Cov:33
GnomAD2 exomes	AF: 0.000220	AC:53	Hom:	AN:240912	Cov:
GnomAD4 exome	AF: 0.0000358	AC:52	Hom:0	AN:1452552	Cov:35
GnomAD4 genome	AF: 0.0000789	AC:12	Hom:0	AN:152162	Cov:33
TOPMed (Bravo)	AF: 0.000151	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:42552	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.00443	AC:	Hom:	AN:	Cov:
Korea4K (4,157 Koreans)	AF: 0.000691	AC:5	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000250	AC:3	Hom:0	AN:122070	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00402	AC:36	Hom:0	AN:8960	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000715	3	41956	0.0000897	6	66886
SCHEMA(Schizophrenia)	0.00116	130	112160	0.000607	112	184584

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.1
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.032
DANN	Benign	0.74
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
FuncVEP CTI	Benign	0.037
GPN-Star LLR	N/A	-1.7
GPN-Star score	N/A	1.7
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Benign	0.55	N
PhyloP100	Benign	-1.5
popEVE	Benign	-2.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.0080
Sift	Benign	0.11	T
Sift4G	Benign	0.26	T
Varity_R	N/A	0.053
VESM-3B	Benign	-3.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs532663391;

hg19: chr22-43525228;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar