14-24576180-C-G

Position:

• chr14-24576180-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001911.3(CTSG):​c.44G>C​(p.Gly15Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,610,484 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: CTSG NM_001911.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.688

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=0.0033926964).
• BP6: Variant 14-24576180-C-G is Benign according to our data. Variant chr14-24576180-C-G is described in ClinVar as [Benign]. Clinvar id is 776828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0145 (2214/152230) while in subpopulation AFR AF= 0.0506 (2103/41532). AF 95% confidence interval is 0.0488. There are 57 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 57 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSG	NM_001911.3	c.44G>C	p.Gly15Ala	missense_variant	1/5	ENST00000216336.3
CTSG	XM_011536499.2	c.44G>C	p.Gly15Ala	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSG	ENST00000216336.3	c.44G>C	p.Gly15Ala	missense_variant	1/5	1	NM_001911.3	P1
CTSG	ENST00000552252.1	n.71G>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2211 AN: 152112 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00373 AC: 910 AN: 244130 Hom.: 17 AF XY: 0.00277 AC XY: 364 AN XY: 131590

Gnomad AFR exome AF: 0.0513

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000905

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00144 AC: 2094 AN: 1458254 Hom.: 39 Cov.: 30 AF XY: 0.00129 AC XY: 934 AN XY: 724842

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000941

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.00332

GnomAD4 genome AF: 0.0145 AC: 2214 AN: 152230 Hom.: 57 Cov.: 32 AF XY: 0.0141 AC XY: 1048 AN XY: 74412

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00253 Hom.: 5

Bravo AF: 0.0168

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00456 AC: 553

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.2
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.95	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.16
Sift	Uncertain	0.027	D
Sift4G	Benign	0.38	T
Polyphen		0.12	B
Vest4		0.098
MVP		0.91
MPC		1.3
ClinPred		0.020	T
GERP RS		1.1
Varity_R		0.089
gMVP		0.67

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: rs61737123; hg19: chr14-25045386;