22-43128615-C-T

Variant names:

• chr22-43128615-C-T
• rs368572843
• NM_001197.5:c.380C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001197.5(BIK):​c.380C>T​(p.Pro127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: BIK NM_001197.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.261

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050059915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIK	NM_001197.5	c.380C>T	p.Pro127Leu	missense_variant	Exon 4 of 5	ENST00000216115.3	NP_001188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIK	ENST00000216115.3	c.380C>T	p.Pro127Leu	missense_variant	Exon 4 of 5	1	NM_001197.5	ENSP00000216115.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248724 AF XY: 0.0000149

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458180 Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3 AN XY: 725116

Gnomad4 AFR exome AF: 0.0000899 AC: 3 AN: 33362

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44328

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25898

Gnomad4 EAS exome AF: 0.0000505 AC: 2 AN: 39602

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85972

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53364

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1109704

Gnomad4 Remaining exome AF: 0.0000996 AC: 6 AN: 60214

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

Gnomad4 AFR AF: 0.000217 AC: 0.000217108 AN: 0.000217108

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654022 AN: 0.0000654022

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380C>T (p.P127L) alteration is located in exon 4 (coding exon 3) of the BIK gene. This alteration results from a C to T substitution at nucleotide position 380, causing the proline (P) at amino acid position 127 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.8
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.027
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0040	B
Vest4		0.051
MVP		0.27
MPC		0.015
ClinPred		0.053	T
GERP RS		-2.5
Varity_R		0.075
gMVP		0.016
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

Publications

LitVar

Other links and lift over

dbSNP: rs368572843; hg19: chr22-43524621;