14-24574745-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001911.3(CTSG):c.269C>T(p.Thr90Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,198 control chromosomes in the GnomAD database, including 79 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 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (35 hom.)
• Consequence: CTSG NM_001911.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.656

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046714544).
• BP6: Variant 14-24574745-G-A is Benign according to our data. Variant chr14-24574745-G-A is described in ClinVar as [Benign]. Clinvar id is 776827.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1932/152330) while in subpopulation AFR AF= 0.0441 (1834/41574). AF 95% confidence interval is 0.0424. There are 44 homozygotes in gnomad4. There are 925 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSG	NM_001911.3	c.269C>T	p.Thr90Ile	missense_variant	3/5	ENST00000216336.3
CTSG	XM_011536499.2	c.311C>T	p.Thr104Ile	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSG	ENST00000216336.3	c.269C>T	p.Thr90Ile	missense_variant	3/5	1	NM_001911.3	P1
CTSG	ENST00000552252.1	n.750C>T		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1929 AN: 152212 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

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: 0.000176

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00354 AC: 891 AN: 251474 Hom.: 14 AF XY: 0.00272 AC XY: 370 AN XY: 135918

Gnomad AFR exome AF: 0.0479

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00128 AC: 1874 AN: 1461868 Hom.: 35 Cov.: 34 AF XY: 0.00116 AC XY: 842 AN XY: 727236

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.0127 AC: 1932 AN: 152330 Hom.: 44 Cov.: 32 AF XY: 0.0124 AC XY: 925 AN XY: 74482

Gnomad4 AFR AF: 0.0441

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00262 Hom.: 13

Bravo AF: 0.0146

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00429 AC: 521

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.087	T
Polyphen		0.070	B
Vest4		0.18
MVP		0.92
MPC		0.77
ClinPred		0.024	T
GERP RS		2.2
Varity_R		0.19
gMVP		0.71

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: rs61737120; hg19: chr14-25043951;