rs2236338

Positions:

• chr14-24631076-A-G
• chr14-24631076-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004131.6(GZMB):​c.739T>C​(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: 𝑓 0.25 (5074 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41531 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.798

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]

GZMB (HGNC:):

ACMG classification

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
GZMB	NM_004131.6	c.739T>C	p.Tyr247His	missense_variant	5/5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.703T>C	p.Tyr235His	missense_variant	5/5		NP_001332940.1
GZMB	NR_144343.2	n.633T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.739T>C	p.Tyr247His	missense_variant	5/5	1	NM_004131.6	ENSP00000216341.4

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38572 AN: 151936 Hom.: 5052 Cov.: 32

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

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

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

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;.;.;.
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

Other links and lift over

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