chr17-75501639-C-G

Variant names:

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

Variant summary

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

The NM_020753.5(CASKIN2):​c.3347G>C​(p.Gly1116Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000014 (0 hom.)
• Consequence: CASKIN2 NM_020753.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05

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=0.2101548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5	c.3347G>C	p.Gly1116Ala	missense_variant	Exon 19 of 20	ENST00000321617.8	NP_065804.2
CASKIN2	NM_001142643.3	c.3101G>C	p.Gly1034Ala	missense_variant	Exon 18 of 19		NP_001136115.1
CASKIN2	XM_047436459.1	c.3347G>C	p.Gly1116Ala	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	c.3347G>C	p.Gly1116Ala	missense_variant	Exon 19 of 20	1	NM_020753.5	ENSP00000325355.3
CASKIN2	ENST00000433559.6	c.3101G>C	p.Gly1034Ala	missense_variant	Exon 18 of 19	2		ENSP00000406963.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 239364 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130962

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: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438698 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712734

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: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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	0.20
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0045	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.12
Sift	Benign	0.16	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.60	P;.
Vest4		0.34
MutPred		0.24		Loss of glycosylation at S1115 (P = 0.0499);.;
MVP		0.71
MPC		0.62
ClinPred		0.28	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776078286; hg19: chr17-73497720;