chr2-42048839-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_138370.3(PKDCC):c.639+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000617 in 1,457,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

PKDCC
NM_138370.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.23

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 22, new splice context is: gggGTaacg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-42048839-G-T is Pathogenic according to our data. Variant chr2-42048839-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKDCC	NM_138370.3 link	c.639+1G>T		splice_donor_variant, intron_variant	Intron 1 of 6	ENST00000294964.6	NP_612379.2	Q504Y2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKDCC	ENST00000294964.6 link	c.639+1G>T	splice_donor_variant, intron_variant	Intron 1 of 6	1	NM_138370.3	ENSP00000294964.5	Q504Y2
PKDCC	ENST00000401498.6 link	n.497+1G>T	splice_donor_variant, intron_variant	Intron 2 of 7	5		ENSP00000385220.2	F8WB71
PKDCC	ENST00000485578.1 link	n.260+1G>T	splice_donor_variant, intron_variant	Intron 1 of 1	2
PKDCC	ENST00000492861.1 link	n.65+1G>T	splice_donor_variant, intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000378

AC:

AN:

158918

Hom.:

AF XY:

0.0000345

AC XY:

AN XY:

86940

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000613

AC:

AN:

1305406

Hom.:

Cov.:

AF XY:

0.00000781

AC XY:

AN XY:

640114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000153

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000152

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.71e-7

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000335

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Nov 09, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.639+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 1 of the PKDCC gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.004% (6/158918) total alleles studied. The highest observed frequency was 0.027% (6/22264) of Latino alleles. This variant has been identified in trans with another PKDCC variant in an individual with short stature, macrocephaly, rhizomelia, and brachydactyly (Pagnamenta, 2023). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 1 of the PKDCC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKDCC are known to be pathogenic (PMID: 19097194, 30478137). This variant is present in population databases (rs763243200, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with clinical features of PKDCC-related skeletal dysplasia (PMID: 30478137; Invitae). ClinVar contains an entry for this variant (Variation ID: 522098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Rhizomelic limb shortening with dysmorphic features

Pathogenic:1

Apr 25, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

GERP RS

3.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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