Genetic Variant BIK:p.Glu134Lys (chr22-43129222-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

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 frequency of 0.0000517 in 1,604,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

BIK
NM_001197.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.45

Publications

2 publications found

Variant links:

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

BIK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.010476798).

BS2

High AC in GnomAd4 at 19 AD gene.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	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

Ensembl Transcripts

Selected	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

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000969

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000129

AC:

AN:

240912

AF XY:

0.000114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000989

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000441

AC:

AN:

1452552

Hom.:

Cov.:

AF XY:

0.0000553

AC XY:

AN XY:

722952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.000157

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000454

AC:

AN:

39684

South Asian (SAS)

AF:

0.000313

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5178

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111822

Other (OTH)

AF:

0.0000332

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41520

American (AMR)

AF:

0.000589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000971

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000754

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.400G>A (p.E134K) alteration is located in exon 5 (coding exon 4) of the BIK gene. This alteration results from a G to A substitution at nucleotide position 400, causing the glutamic acid (E) at amino acid position 134 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.030

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.060

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.43

M_CAP

Benign

0.0044

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-1.5

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.060

REVEL

Benign

0.0070

Sift

Benign

0.38

Sift4G

Benign

0.66

Polyphen

0.013

Vest4

0.092

MutPred

0.45

Gain of methylation at E134 (P = 0.0014)

MVP

0.14

MPC

0.013

ClinPred

0.028

GERP RS

-8.5

Varity_R

0.031

gMVP

0.031

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over