16-2179002-C-A

Position:

• chr16-2179002-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020764.4(CASKIN1):​c.4099G>T​(p.Asp1367Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CASKIN1 NM_020764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

CASKIN1 (HGNC:20879): (CASK interacting protein 1) Enables identical protein binding activity. Predicted to be involved in signal transduction. Predicted to be active in cytoplasm and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37848747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASKIN1	NM_020764.4	c.4099G>T	p.Asp1367Tyr	missense_variant	19/20	ENST00000343516.8	NP_065815.1
CASKIN1	XM_024450361.2	c.3886G>T	p.Asp1296Tyr	missense_variant	17/18		XP_024306129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASKIN1	ENST00000343516.8	c.4099G>T	p.Asp1367Tyr	missense_variant	19/20	1	NM_020764.4	ENSP00000345436	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095654 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 523612

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: 0.0000339

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.4099G>T (p.D1367Y) alteration is located in exon 19 (coding exon 19) of the CASKIN1 gene. This alteration results from a G to T substitution at nucleotide position 4099, causing the aspartic acid (D) at amino acid position 1367 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.76
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.026	D
Polyphen		0.89	P
Vest4		0.34
MutPred		0.091		Gain of phosphorylation at D1367 (P = 0.0198);
MVP		0.63
MPC		0.34
ClinPred		0.61	D
GERP RS		3.1
Varity_R		0.22
gMVP		0.43

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: rs2093156348; hg19: chr16-2229003;