Genetic Variant CACTIN:p.Asp321Glu (chr19-3619164-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001080543.2(CACTIN):c.963T>G(p.Asp321Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D321N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACTIN
NM_001080543.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41093427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACTIN	NM_001080543.2 link	c.963T>G	p.Asp321Glu	missense_variant	Exon 5 of 10	ENST00000429344.7	NP_001074012.1	Q8WUQ7-1
CACTIN	NM_021231.2 link	c.963T>G	p.Asp321Glu	missense_variant	Exon 5 of 11		NP_067054.1	Q8WUQ7-1
CACTIN	XM_011528160.3 link	c.963T>G	p.Asp321Glu	missense_variant	Exon 5 of 8		XP_011526462.1
CACTIN	XM_011528161.3 link	c.963T>G	p.Asp321Glu	missense_variant	Exon 5 of 7		XP_011526463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACTIN	ENST00000429344.7 link	c.963T>G	p.Asp321Glu	missense_variant	Exon 5 of 10	1	NM_001080543.2	ENSP00000415078.1		Q8WUQ7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1460116

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.963T>G (p.D321E) alteration is located in exon 5 (coding exon 5) of the CACTIN gene. This alteration results from a T to G substitution at nucleotide position 963, causing the aspartic acid (D) at amino acid position 321 to be replaced by a glutamic acid (E). 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

T;T;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.075

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

.;.;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

L;L;L;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.0

N;N;.;.

REVEL

Benign

0.20

Sift

Benign

0.22

T;T;.;.

Sift4G

Benign

0.96

T;T;T;.

Polyphen

0.92

P;P;P;.

Vest4

0.71

MutPred

0.52

Gain of disorder (P = 0.1286);Gain of disorder (P = 0.1286);Gain of disorder (P = 0.1286);.;

MVP

0.24

MPC

1.5

ClinPred

0.59

GERP RS

3.7

Varity_R

0.066

gMVP

0.75

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