Genetic Variant CASKIN2:p.Thr1026Asn (chr17-75501997-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_020753.5(CASKIN2):c.3077C>A(p.Thr1026Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,460,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CASKIN2
NM_020753.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.430

Variant links:

Genes affected

CASKIN2 (HGNC:18200): (CASK interacting protein 2) This gene encodes a large protein that contains six ankyrin repeats, as well as a Src homology 3 (SH3) domain and two sterile alpha motif (SAM) domains, which may be involved in protein-protein interactions. The C-terminal portion of this protein is proline-rich and contains a conserved region. A related protein interacts with calcium/calmodulin-dependent serine protein kinase (CASK). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

CASKIN2 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=0.06334895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5 link	c.3077C>A	p.Thr1026Asn	missense_variant	Exon 18 of 20	ENST00000321617.8	NP_065804.2	Q8WXE0-1
CASKIN2	NM_001142643.3 link	c.2831C>A	p.Thr944Asn	missense_variant	Exon 17 of 19		NP_001136115.1	Q8WXE0-2
CASKIN2	XM_047436459.1 link	c.3077C>A	p.Thr1026Asn	missense_variant	Exon 18 of 20		XP_047292415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASKIN2	ENST00000321617.8 link	c.3077C>A	p.Thr1026Asn	missense_variant	Exon 18 of 20	1	NM_020753.5	ENSP00000325355.3		Q8WXE0-1
CASKIN2	ENST00000433559.6 link	c.2831C>A	p.Thr944Asn	missense_variant	Exon 17 of 19	2		ENSP00000406963.2		Q8WXE0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247796

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134676

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:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1460342

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726402

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3077C>A (p.T1026N) alteration is located in exon 18 (coding exon 17) of the CASKIN2 gene. This alteration results from a C to A substitution at nucleotide position 3077, causing the threonine (T) at amino acid position 1026 to be replaced by an asparagine (N). 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

0.078

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.6

DANN

Benign

0.70

DEOGEN2

Benign

0.0053

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.33

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.063

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.067

Sift

Benign

0.51

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.0

B;.

Vest4

0.081

MutPred

0.22

Loss of glycosylation at T1026 (P = 0.0011);.;

MVP

0.26

MPC

0.15

ClinPred

0.029

GERP RS

2.9

Varity_R

0.030

gMVP

0.10

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