chr19-3623913-G-C

Position:

chr19-3623913-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080543.2(CACTIN):c.417C>G(p.Ser139Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000872 in 1,606,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CACTIN
NM_001080543.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

CACTIN (HGNC:29938): (cactin, spliceosome C complex subunit) Enables RNA binding activity. Involved in several processes, including cellular response to cytokine stimulus; negative regulation of cytokine production; and negative regulation of signal transduction. Located in cytosol and nuclear speck. Part of catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

CACTIN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06488702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACTIN	NM_001080543.2 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/10	ENST00000429344.7	NP_001074012.1
CACTIN	NM_021231.2 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/11		NP_067054.1
CACTIN	XM_011528160.3 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/8		XP_011526462.1
CACTIN	XM_011528161.3 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/7		XP_011526463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACTIN	ENST00000429344.7 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/10	1	NM_001080543.2	ENSP00000415078	P1	Q8WUQ7-1
CACTIN	ENST00000221899.7 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/12	1		ENSP00000221899	P1	Q8WUQ7-1
CACTIN	ENST00000585942.5 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant, NMD_transcript_variant	2/12	1		ENSP00000465751		Q8WUQ7-1
CACTIN	ENST00000248420.9 linkuse as main transcript	c.417C>G	p.Ser139Arg	missense_variant	2/11	5		ENSP00000248420	P1	Q8WUQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000294

AC:

AN:

237828

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

130808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000551

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1453968

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723688

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000452

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000416

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.417C>G (p.S139R) alteration is located in exon 2 (coding exon 2) of the CACTIN gene. This alteration results from a C to G substitution at nucleotide position 417, causing the serine (S) at amino acid position 139 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0088

T;T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.70

.;.;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.065

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

L;L;L

MutationTaster

Benign

0.60

D;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.15

N;N;.

REVEL

Benign

0.061

Sift

Benign

0.41

T;T;.

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.26

MutPred

0.26

Loss of phosphorylation at S139 (P = 0.0252);Loss of phosphorylation at S139 (P = 0.0252);Loss of phosphorylation at S139 (P = 0.0252);

MVP

0.11

MPC

0.70

ClinPred

0.11

GERP RS

-0.049

Varity_R

0.051

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over