rs202068245

chr1-205211483-G-Achr1-205211483-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015375.3(DSTYK):c.53C>T(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,585,060 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: DSTYK NM_015375.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.983

Genes affected

DSTYK (HGNC:29043): (dual serine/threonine and tyrosine protein kinase) This gene encodes a dual serine/threonine and tyrosine protein kinase which is expressed in multiple tissues. It is thought to function as a regulator of cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006824583).
• BP6: Variant 1-205211483-G-A is Benign according to our data. Variant chr1-205211483-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224358.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSTYK	NM_015375.3	c.53C>T	p.Pro18Leu	missense_variant	1/13	ENST00000367162.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSTYK	ENST00000367162.8	c.53C>T	p.Pro18Leu	missense_variant	1/13	1	NM_015375.3	P1
DSTYK	ENST00000367161.7	c.53C>T	p.Pro18Leu	missense_variant	1/12	1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000915 AC: 184 AN: 201072 Hom.: 2 AF XY: 0.000909 AC XY: 101 AN XY: 111096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000222

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.000417 AC: 598 AN: 1432726 Hom.: 2 Cov.: 32 AF XY: 0.000418 AC XY: 297 AN XY: 711326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000210

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000853

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000540

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000717 AC: 6

ExAC AF: 0.000518 AC: 61

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DSTYK: BS1 -

Congenital anomalies of kidney and urinary tract 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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DSTYK-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.31	T;T
Polyphen		0.40	B;B
Vest4		0.30
MVP		0.55
MPC		0.39
ClinPred		0.086	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.36

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: rs202068245; hg19: chr1-205180611; COSMIC: COSV65686225;