17-75501991-C-T

Variant names:

• chr17-75501991-C-T
• rs909160755
• NM_020753.5:c.3083G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020753.5(CASKIN2):​c.3083G>A​(p.Gly1028Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASKIN2 NM_020753.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779

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

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=0.06705329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5	c.3083G>A	p.Gly1028Asp	missense_variant	Exon 18 of 20	ENST00000321617.8	NP_065804.2
CASKIN2	NM_001142643.3	c.2837G>A	p.Gly946Asp	missense_variant	Exon 17 of 19		NP_001136115.1
CASKIN2	XM_047436459.1	c.3083G>A	p.Gly1028Asp	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	c.3083G>A	p.Gly1028Asp	missense_variant	Exon 18 of 20	1	NM_020753.5	ENSP00000325355.3
CASKIN2	ENST00000433559.6	c.2837G>A	p.Gly946Asp	missense_variant	Exon 17 of 19	2		ENSP00000406963.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134512

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: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460048 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 726222

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.9
DANN	Benign	0.46
DEOGEN2	Benign	0.0047	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.54	N;N
REVEL	Benign	0.10
Sift	Benign	0.63	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MutPred		0.17		Gain of solvent accessibility (P = 0.0638);.;
MVP		0.24
MPC		0.19
ClinPred		0.053	T
GERP RS		4.2
Varity_R		0.033
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs909160755; hg19: chr17-73498072;