rs532663391

Variant names:

• chr22-43129222-G-A
• rs532663391
• NM_001197.5:c.400G>A
• BIK p.Glu134Lys

Your query was ambiguous. Multiple possible variants found:

• chr22-43129222-G-A
• chr22-43129222-G-C

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>A (p.Glu134Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000517 (AC=83) in the gnomAD database across 1,604,712 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000382. 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 (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E134Q: unknown significance (ClinVar VariationId 4459454) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Adenomas and Adenocarcinomas.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: BIK NM_001197.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 = 83 (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>A	p.Glu134Lys	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>A	p.Glu134Lys	missense	Exon 5 of 5	ENSP00000216115.2	Q13323
	BIK	ENST00000918052.1		c.514G>A	p.Glu172Lys	missense	Exon 6 of 6	ENSP00000588111.1	A0ACI8SWR1
	BIK	ENST00000910665.1		c.400G>A	p.Glu134Lys	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: 0.000125	AC:19	Hom:0	AN:152042	Cov:33
GnomAD2 exomes	AF: 0.000129	AC:31	Hom:	AN:240912	Cov:
GnomAD4 exome	AF: 0.0000441	AC:64	Hom:0	AN:1452552	Cov:35
GnomAD4 genome	AF: 0.000125	AC:19	Hom:0	AN:152160	Cov:33
TOPMed (Bravo)	AF: 0.000106	AC:28	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000705	AC:3	Hom:0	AN:42552	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000591	AC:	Hom:	AN:	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Turkish Variome	AF: 0.000647	AC:1	Hom:0	AN:1546	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000893	AC:8	Hom:0	AN:8960	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000715	3	41956	0.0000150	1	66886
SCHEMA(Schizophrenia)	0.000256	29	113186	0.0000892	17	190514

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

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.1
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.030
DANN	Benign	0.78
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.016	N
FuncVEP CTI	Benign	0.0030
GPN-Star LLR	N/A	-1.5
GPN-Star score	N/A	1.5
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	99/1	polymorphism
MutationAssessor	Benign	0.20	N
PhyloP100	Benign	-1.5
popEVE	Benign	-2.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.0070
Sift	Benign	0.38	T
Sift4G	Benign	0.66	T
Varity_R	N/A	0.031
VESM-3B	Benign	-5.0

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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;

COSMIC: COSV51792892;

COSMIC: COSV51792892;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar