2-42048216-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_138370.3(PKDCC):c.17C>T(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000952 in 1,207,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000052 ( 1 hom. )

Consequence

PKDCC
NM_138370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.409

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

rhizomelic limb shortening with dysmorphic features
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

PKDCC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04208821).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00041 (60/146448) while in subpopulation AFR AF = 0.00135 (55/40808). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138370.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKDCC	NM_138370.3	MANE Select	c.17C>T	p.Ala6Val	missense	Exon 1 of 7	NP_612379.2	Q504Y2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKDCC	ENST00000294964.6	TSL:1 MANE Select	c.17C>T	p.Ala6Val	missense	Exon 1 of 7	ENSP00000294964.5	Q504Y2
PKDCC	ENST00000914294.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 7	ENSP00000584353.1
PKDCC	ENST00000953637.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 7	ENSP00000623696.1

Frequencies

GnomAD3 genomes

AF:

0.000383

AC:

AN:

146348

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000494

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

30624

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000518

AC:

AN:

1060996

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

515532

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

20450

American (AMR)

AF:

0.000157

AC:

AN:

12766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12802

East Asian (EAS)

AF:

0.00

AC:

AN:

17880

South Asian (SAS)

AF:

0.0000511

AC:

AN:

39112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18616

Middle Eastern (MID)

AF:

0.000752

AC:

AN:

2658

European-Non Finnish (NFE)

AF:

0.00000223

AC:

AN:

897584

Other (OTH)

AF:

0.000256

AC:

AN:

39128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000410

AC:

AN:

146448

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

AN XY:

71306

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

40808

American (AMR)

AF:

0.000203

AC:

AN:

14796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

4980

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8660

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65788

Other (OTH)

AF:

0.000489

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000393

ExAC

AF:

0.0000706

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.047

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.45

M_CAP

Benign

0.031

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

0.41

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.30

REVEL

Benign

0.036

Sift

Benign

0.82

Sift4G

Benign

1.0

Polyphen

0.14

Vest4

0.072

MutPred

0.26

Loss of helix (P = 0.0138)

MVP

0.52

MPC

1.8

ClinPred

0.065

GERP RS

2.6

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.057

gMVP

0.29

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over