2-42048424-C-CG

Variant names:

• chr2-42048424-C-CG
• NM_138370.3:c.228dupG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138370.3(PKDCC):​c.228dupG​(p.Pro77AlafsTer95) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 973,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: PKDCC NM_138370.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.263

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-42048424-C-CG is Pathogenic according to our data. Variant chr2-42048424-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803946.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKDCC	NM_138370.3	c.228dupG	p.Pro77AlafsTer95	frameshift_variant	Exon 1 of 7	ENST00000294964.6	NP_612379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKDCC	ENST00000294964.6	c.228dupG	p.Pro77AlafsTer95	frameshift_variant	Exon 1 of 7	1	NM_138370.3	ENSP00000294964.5
PKDCC	ENST00000401498.6	n.198+30dupG		intron_variant	Intron 1 of 7	5		ENSP00000385220.2
PKDCC	ENST00000485578.1	n.-155_-154insG		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 973354 Hom.: 0 Cov.: 30 AF XY: 0.00000215 AC XY: 1 AN XY: 464314

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: 0.0000460

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhizomelic limb shortening with dysmorphic features Pathogenic:1

Nov 28, 2022

Clinical and Biomedical Sciences, University of Exeter

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sajan et al. (2019) reported 2 unrelated patients with rhizomelic limb shortening, variable dysmorphic features and biallelic predicted loss of function variants in PKDCC. Short limbs were previously described in a mouse model (Imuta et al, 2009). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-42275564;