chr14-24632423-T-C

Variant names:

• chr14-24632423-T-C
• rs10909625
• NM_004131.6:c.240A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004131.6(GZMB):​c.240A>G​(p.Lys80Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,547,436 control chromosomes in the GnomAD database, including 47,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5458 hom., cov: 30)
  • Exomes 𝑓: 0.22 (41625 hom.)
• Consequence: GZMB NM_004131.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.39
• Publications: 25 publications found

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]

ENSG00000258657 (HGNC:58166):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 14-24632423-T-C is Benign according to our data. Variant chr14-24632423-T-C is described in ClinVar as Benign. ClinVar VariationId is 769859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004131.6. 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
	GZMB	NM_004131.6	MANE Select	c.240A>G	p.Lys80Lys	synonymous	Exon 3 of 5	NP_004122.2
	GZMB	NM_001346011.2		c.204A>G	p.Lys68Lys	synonymous	Exon 3 of 5	NP_001332940.1
	GZMB	NR_144343.2		n.234-305A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	ENST00000216341.9	TSL:1 MANE Select	c.240A>G	p.Lys80Lys	synonymous	Exon 3 of 5	ENSP00000216341.4
	GZMB	ENST00000415355.7	TSL:2	c.204A>G	p.Lys68Lys	synonymous	Exon 3 of 5	ENSP00000387385.3
	GZMB	ENST00000530830.1	TSL:5	n.*163A>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000435084.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39593 AN: 151342 Hom.: 5442 Cov.: 30

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.181 AC: 37916 AN: 209180 AF XY: 0.183

Gnomad AFR exome AF: 0.325

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.223 AC: 310642 AN: 1395976 Hom.: 41625 Cov.: 34 AF XY: 0.224 AC XY: 154845 AN XY: 691252

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.353 AC: 10987 AN: 31136

American (AMR) AF: 0.118 AC: 4808 AN: 40644

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 5646 AN: 23836

East Asian (EAS) AF: 0.218 AC: 8369 AN: 38448

South Asian (SAS) AF: 0.297 AC: 23444 AN: 78818

European-Finnish (FIN) AF: 0.186 AC: 9521 AN: 51326

Middle Eastern (MID) AF: 0.303 AC: 1663 AN: 5488

European-Non Finnish (NFE) AF: 0.217 AC: 232161 AN: 1068400

Other (OTH) AF: 0.243 AC: 14043 AN: 57880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.262 AC: 39653 AN: 151460 Hom.: 5458 Cov.: 30 AF XY: 0.258 AC XY: 19096 AN XY: 73986

African (AFR) AF: 0.351 AC: 14472 AN: 41174

American (AMR) AF: 0.199 AC: 3030 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 864 AN: 3466

East Asian (EAS) AF: 0.268 AC: 1375 AN: 5128

South Asian (SAS) AF: 0.328 AC: 1561 AN: 4756

European-Finnish (FIN) AF: 0.188 AC: 1980 AN: 10518

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.229 AC: 15578 AN: 67886

Other (OTH) AF: 0.278 AC: 585 AN: 2104

Alfa AF: 0.248 Hom.: 1887

Bravo AF: 0.267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.1
DANN	Benign	0.43
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10909625; hg19: chr14-25101629; COSMIC: COSV53540581;