rs45567233

Positions:

• chr14-24574465-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001911.3(CTSG):​c.374A>G​(p.Asn125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0702 in 1,613,820 control chromosomes in the GnomAD database, including 4,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.061 (342 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4192 hom.)
• Consequence: CTSG NM_001911.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0310

Genes affected

CTSG (HGNC:2532): (cathepsin G) The protein encoded by this gene, a member of the peptidase S1 protein family, is found in azurophil granules of neutrophilic polymorphonuclear leukocytes. The encoded protease has a specificity similar to that of chymotrypsin C, and may participate in the killing and digestion of engulfed pathogens, and in connective tissue remodeling at sites of inflammation. In addition, the encoded protein is antimicrobial, with bacteriocidal activity against S. aureus and N. gonorrhoeae. Transcript variants utilizing alternative polyadenylation signals exist for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003850907).
• BP6: Variant 14-24574465-T-C is Benign according to our data. Variant chr14-24574465-T-C is described in ClinVar as [Benign]. Clinvar id is 402574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSG	NM_001911.3	c.374A>G	p.Asn125Ser	missense_variant	4/5	ENST00000216336.3	NP_001902.1
CTSG	XM_011536499.2	c.416A>G	p.Asn139Ser	missense_variant	4/5		XP_011534801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSG	ENST00000216336.3	c.374A>G	p.Asn125Ser	missense_variant	4/5	1	NM_001911.3	ENSP00000216336	P1
CTSG	ENST00000552252.1	n.855A>G		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0613 AC: 9313 AN: 152004 Hom.: 338 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0995

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.0651

GnomAD3 exomes AF: 0.0801 AC: 20015 AN: 249924 Hom.: 953 AF XY: 0.0795 AC XY: 10744 AN XY: 135070

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.0987

Gnomad FIN exome AF: 0.0771

Gnomad NFE exome AF: 0.0693

Gnomad OTH exome AF: 0.0693

GnomAD4 exome AF: 0.0711 AC: 103994 AN: 1461698 Hom.: 4192 Cov.: 34 AF XY: 0.0716 AC XY: 52067 AN XY: 727142

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.0992

Gnomad4 ASJ exome AF: 0.0349

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.0972

Gnomad4 FIN exome AF: 0.0784

Gnomad4 NFE exome AF: 0.0664

Gnomad4 OTH exome AF: 0.0677

GnomAD4 genome AF: 0.0613 AC: 9328 AN: 152122 Hom.: 342 Cov.: 32 AF XY: 0.0628 AC XY: 4675 AN XY: 74388

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.0716

Gnomad4 ASJ AF: 0.0406

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.0986

Gnomad4 FIN AF: 0.0794

Gnomad4 NFE AF: 0.0654

Gnomad4 OTH AF: 0.0696

Alfa AF: 0.0665 Hom.: 620

Bravo AF: 0.0600

TwinsUK AF: 0.0645 AC: 239

ALSPAC AF: 0.0698 AC: 269

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.0607 AC: 522

ExAC AF: 0.0809 AC: 9821

Asia WGS AF: 0.140 AC: 485 AN: 3478

EpiCase AF: 0.0625

EpiControl AF: 0.0628

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.4
DANN	Benign	0.37
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.64	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.11
Sift	Benign	0.40	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.35
ClinPred		0.0059	T
GERP RS		0.13
Varity_R		0.15
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs45567233; hg19: chr14-25043671;