17-75501817-G-T

Variant names:

• chr17-75501817-G-T
• rs199651519
• NM_020753.5:c.3257C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020753.5(CASKIN2):​c.3257C>A​(p.Pro1086Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,396,280 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: CASKIN2 NM_020753.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.178

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08738828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5	c.3257C>A	p.Pro1086Gln	missense_variant	Exon 18 of 20	ENST00000321617.8	NP_065804.2
CASKIN2	NM_001142643.3	c.3011C>A	p.Pro1004Gln	missense_variant	Exon 17 of 19		NP_001136115.1
CASKIN2	XM_047436459.1	c.3257C>A	p.Pro1086Gln	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.3257C>A	p.Pro1086Gln	missense_variant	Exon 18 of 20	1	NM_020753.5	ENSP00000325355.3
CASKIN2	ENST00000433559.6	c.3011C>A	p.Pro1004Gln	missense_variant	Exon 17 of 19	2		ENSP00000406963.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000501 AC: 7 AN: 1396280 Hom.: 0 Cov.: 51 AF XY: 0.00000581 AC XY: 4 AN XY: 688092

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: 9.24e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.086
Sift	Benign	0.076	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.0010	B;.
Vest4		0.11
MutPred		0.25		Loss of glycosylation at P1086 (P = 0.0118);.;
MVP		0.35
MPC		0.12
ClinPred		0.066	T
GERP RS		0.92
Varity_R		0.062
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

Other links and lift over

dbSNP: rs199651519; hg19: chr17-73497898;