Genetic Variant NM_020753.5:c.3347G>A (chr17-75501639-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_020753.5(CASKIN2):c.3347G>A(p.Gly1116Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CASKIN2
NM_020753.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

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 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=0.39699894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5 link	c.3347G>A	p.Gly1116Asp	missense_variant	Exon 19 of 20	ENST00000321617.8	NP_065804.2	Q8WXE0-1
CASKIN2	NM_001142643.3 link	c.3101G>A	p.Gly1034Asp	missense_variant	Exon 18 of 19		NP_001136115.1	Q8WXE0-2
CASKIN2	XM_047436459.1 link	c.3347G>A	p.Gly1116Asp	missense_variant	Exon 19 of 20		XP_047292415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASKIN2	ENST00000321617.8 link	c.3347G>A	p.Gly1116Asp	missense_variant	Exon 19 of 20	1	NM_020753.5	ENSP00000325355.3		Q8WXE0-1
CASKIN2	ENST00000433559.6 link	c.3101G>A	p.Gly1034Asp	missense_variant	Exon 18 of 19	2		ENSP00000406963.2		Q8WXE0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239364

Hom.:

AF XY:

0.00000764

AC XY:

AN XY:

130962

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:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3347G>A (p.G1116D) alteration is located in exon 19 (coding exon 18) of the CASKIN2 gene. This alteration results from a G to A substitution at nucleotide position 3347, causing the glycine (G) at amino acid position 1116 to be replaced by an aspartic acid (D). 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

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.97

L;.

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.074

T;T

Polyphen

1.0

D;.

Vest4

0.53

MutPred

0.31

Gain of relative solvent accessibility (P = 0.0215);.;

MVP

0.64

MPC

0.69

ClinPred

0.75

GERP RS

5.6

Varity_R

0.39

gMVP

0.21

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