17-75501997-G-C

Variant names:

• chr17-75501997-G-C
• rs767592305
• NM_020753.5:c.3077C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020753.5(CASKIN2):​c.3077C>G​(p.Thr1026Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1026I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CASKIN2 NM_020753.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.430
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050685495).

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.3077C>G	p.Thr1026Ser	missense	Exon 18 of 20	NP_065804.2	Q8WXE0-1
	CASKIN2	NM_001142643.3		c.2831C>G	p.Thr944Ser	missense	Exon 17 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.3077C>G	p.Thr1026Ser	missense	Exon 18 of 20	ENSP00000325355.3	Q8WXE0-1
	CASKIN2	ENST00000861913.1		c.3140C>G	p.Thr1047Ser	missense	Exon 18 of 20	ENSP00000531972.1
	CASKIN2	ENST00000861914.1		c.3140C>G	p.Thr1047Ser	missense	Exon 18 of 20	ENSP00000531973.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460342 Hom.: 0 Cov.: 50 AF XY: 0.00000275 AC XY: 2 AN XY: 726402

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111644

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.1
DANN	Benign	0.62
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.43
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.058
Sift	Benign	0.73	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of glycosylation at P1025 (P = 0.0831)
MVP		0.26
MPC		0.12
ClinPred		0.034	T
GERP RS		2.9
Varity_R		0.026
gMVP		0.062
Mutation Taster		=97/3	polymorphism

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: rs767592305; hg19: chr17-73498078;