Genetic Variant CASKIN2:p.Glu1040Lys (chr17-75501956-C-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.3118G>A(p.Glu1040Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,605,930 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: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

CASKIN2
NM_020753.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.81

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:

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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=0.053052783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5 link	c.3118G>A	p.Glu1040Lys	missense_variant	Exon 18 of 20	ENST00000321617.8	NP_065804.2	Q8WXE0-1
CASKIN2	NM_001142643.3 link	c.2872G>A	p.Glu958Lys	missense_variant	Exon 17 of 19		NP_001136115.1	Q8WXE0-2
CASKIN2	XM_047436459.1 link	c.3118G>A	p.Glu1040Lys	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.3118G>A	p.Glu1040Lys	missense_variant	Exon 18 of 20	1	NM_020753.5	ENSP00000325355.3		Q8WXE0-1
CASKIN2	ENST00000433559.6 link	c.2872G>A	p.Glu958Lys	missense_variant	Exon 17 of 19	2		ENSP00000406963.2		Q8WXE0-2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000575

AC:

AN:

243570

Hom.:

AF XY:

0.0000606

AC XY:

AN XY:

132026

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000675

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000922

AC:

134

AN:

1453764

Hom.:

Cov.:

AF XY:

0.0000734

AC XY:

AN XY:

722284

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000820

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.0000832

GnomAD4 genome

AF:

0.000118

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3118G>A (p.E1040K) alteration is located in exon 18 (coding exon 17) of the CASKIN2 gene. This alteration results from a G to A substitution at nucleotide position 3118, causing the glutamic acid (E) at amino acid position 1040 to be replaced by a lysine (K). 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

0.080

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.11

Sift

Benign

0.70

T;T

Sift4G

Benign

0.81

T;T

Polyphen

0.0

B;.

Vest4

0.11

MVP

0.25

MPC

0.15

ClinPred

0.87

GERP RS

4.0

Varity_R

0.025

gMVP

0.12

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