chr17-75501639-C-T

Variant names:

• chr17-75501639-C-T
• rs776078286
• NM_020753.5:c.3347G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39699894).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020753.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASKIN2	NM_020753.5	MANE Select	c.3347G>A	p.Gly1116Asp	missense	Exon 19 of 20	NP_065804.2	Q8WXE0-1
	CASKIN2	NM_001142643.3		c.3101G>A	p.Gly1034Asp	missense	Exon 18 of 19	NP_001136115.1	Q8WXE0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASKIN2	ENST00000321617.8	TSL:1 MANE Select	c.3347G>A	p.Gly1116Asp	missense	Exon 19 of 20	ENSP00000325355.3	Q8WXE0-1
	CASKIN2	ENST00000861913.1		c.3410G>A	p.Gly1137Asp	missense	Exon 19 of 20	ENSP00000531972.1
	CASKIN2	ENST00000861914.1		c.3410G>A	p.Gly1137Asp	missense	Exon 19 of 20	ENSP00000531973.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239364 AF XY: 0.00000764

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.074	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	D
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

Other links and lift over

dbSNP: rs776078286; hg19: chr17-73497720;