2-42048324-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_138370.3(PKDCC):c.125C>T(p.Ser42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,190,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000061 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PKDCC
NM_138370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0750

Variant links:

Genes affected

PKDCC (HGNC:25123): (protein kinase domain containing, cytoplasmic) Enables non-membrane spanning protein tyrosine kinase activity. Involved in peptidyl-tyrosine phosphorylation and skeletal system development. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PKDCC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08529577).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000611 (9/147280) while in subpopulation EAS AF= 0.0012 (6/5002). AF 95% confidence interval is 0.000522. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKDCC	NM_138370.3 link	c.125C>T	p.Ser42Leu	missense_variant	Exon 1 of 7	ENST00000294964.6	NP_612379.2	Q504Y2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKDCC	ENST00000294964.6 link	c.125C>T	p.Ser42Leu	missense_variant	Exon 1 of 7	1	NM_138370.3	ENSP00000294964.5		Q504Y2
PKDCC	ENST00000401498.6 link	n.125C>T		non_coding_transcript_exon_variant	Exon 1 of 8	5		ENSP00000385220.2		F8WB71

Frequencies

GnomAD3 genomes

AF:

0.0000612

AC:

AN:

147174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000671

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00120

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1042800

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

498510

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000768

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000112

Gnomad4 OTH exome

AF:

0.0000506

GnomAD4 genome

AF:

0.0000611

AC:

AN:

147280

Hom.:

Cov.:

AF XY:

0.0000697

AC XY:

AN XY:

71734

show subpopulations

Gnomad4 AFR

AF:

0.0000488

Gnomad4 AMR

AF:

0.0000671

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00120

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125C>T (p.S42L) alteration is located in exon 1 (coding exon 1) of the PKDCC gene. This alteration results from a C to T substitution at nucleotide position 125, causing the serine (S) at amino acid position 42 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 42 of the PKDCC protein (p.Ser42Leu). This variant is present in population databases (no rsID available, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PKDCC-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.65

M_CAP

Benign

0.022

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.81

REVEL

Benign

0.050

Sift

Benign

0.11

Sift4G

Benign

0.27

Polyphen

0.77

Vest4

0.067

MutPred

0.17

Loss of phosphorylation at S42 (P = 0.0018);

MVP

0.62

MPC

1.7

ClinPred

0.22

GERP RS

2.1

Varity_R

0.10

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over