rs2236338

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004131.6(GZMB):ā€‹c.739T>Cā€‹(p.Tyr247His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,609,608 control chromosomes in the GnomAD database, including 46,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.25 ( 5074 hom., cov: 32)
Exomes š‘“: 0.23 ( 41531 hom. )

Consequence

GZMB
NM_004131.6 missense

Scores

18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.798
Variant links:
Genes affected
GZMB (HGNC:4709): (granzyme B) This gene encodes a member of the granzyme subfamily of proteins, part of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and proteolytically processed to generate the active protease, which induces target cell apoptosis. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing. Expression of this gene may be elevated in human patients with cardiac fibrosis. [provided by RefSeq, Sep 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0058291852).
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GZMBNM_004131.6 linkuse as main transcriptc.739T>C p.Tyr247His missense_variant 5/5 ENST00000216341.9 NP_004122.2
GZMBNM_001346011.2 linkuse as main transcriptc.703T>C p.Tyr235His missense_variant 5/5 NP_001332940.1
GZMBNR_144343.2 linkuse as main transcriptn.633T>C non_coding_transcript_exon_variant 4/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GZMBENST00000216341.9 linkuse as main transcriptc.739T>C p.Tyr247His missense_variant 5/51 NM_004131.6 ENSP00000216341 P2
ENST00000555300.1 linkuse as main transcriptn.177+7950A>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.254
AC:
38572
AN:
151936
Hom.:
5052
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.325
Gnomad AMI
AF:
0.134
Gnomad AMR
AF:
0.195
Gnomad ASJ
AF:
0.246
Gnomad EAS
AF:
0.282
Gnomad SAS
AF:
0.334
Gnomad FIN
AF:
0.183
Gnomad MID
AF:
0.313
Gnomad NFE
AF:
0.229
Gnomad OTH
AF:
0.266
GnomAD3 exomes
AF:
0.239
AC:
60130
AN:
251230
Hom.:
7638
AF XY:
0.246
AC XY:
33397
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.330
Gnomad AMR exome
AF:
0.147
Gnomad ASJ exome
AF:
0.259
Gnomad EAS exome
AF:
0.281
Gnomad SAS exome
AF:
0.322
Gnomad FIN exome
AF:
0.187
Gnomad NFE exome
AF:
0.234
Gnomad OTH exome
AF:
0.233
GnomAD4 exome
AF:
0.235
AC:
341981
AN:
1457554
Hom.:
41531
Cov.:
30
AF XY:
0.238
AC XY:
172469
AN XY:
725336
show subpopulations
Gnomad4 AFR exome
AF:
0.332
Gnomad4 AMR exome
AF:
0.154
Gnomad4 ASJ exome
AF:
0.260
Gnomad4 EAS exome
AF:
0.236
Gnomad4 SAS exome
AF:
0.320
Gnomad4 FIN exome
AF:
0.192
Gnomad4 NFE exome
AF:
0.228
Gnomad4 OTH exome
AF:
0.251
GnomAD4 genome
AF:
0.254
AC:
38645
AN:
152054
Hom.:
5074
Cov.:
32
AF XY:
0.251
AC XY:
18684
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.325
Gnomad4 AMR
AF:
0.194
Gnomad4 ASJ
AF:
0.246
Gnomad4 EAS
AF:
0.282
Gnomad4 SAS
AF:
0.335
Gnomad4 FIN
AF:
0.183
Gnomad4 NFE
AF:
0.229
Gnomad4 OTH
AF:
0.272
Alfa
AF:
0.242
Hom.:
10710
Bravo
AF:
0.257
TwinsUK
AF:
0.234
AC:
867
ALSPAC
AF:
0.235
AC:
907
ESP6500AA
AF:
0.318
AC:
1401
ESP6500EA
AF:
0.238
AC:
2050
ExAC
AF:
0.246
AC:
29845
Asia WGS
AF:
0.337
AC:
1173
AN:
3478
EpiCase
AF:
0.241
EpiControl
AF:
0.251

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
4.1
DANN
Benign
0.29
DEOGEN2
Benign
0.25
.;T;T;T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.0057
N
LIST_S2
Benign
0.37
T;T;T;.;T
MetaRNN
Benign
0.0058
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.61
.;N;.;.;.
MutationTaster
Benign
1.0
P;P;P;P
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.2
N;N;.;N;.
REVEL
Benign
0.14
Sift
Benign
0.34
T;T;.;T;.
Sift4G
Benign
0.25
T;T;T;T;T
Polyphen
0.0
.;B;.;.;.
Vest4
0.034
MPC
0.24
ClinPred
0.0023
T
GERP RS
-1.6
Varity_R
0.12
gMVP
0.41

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2236338; hg19: chr14-25100282; COSMIC: COSV53540498; COSMIC: COSV53540498; API