chr2-42048424-CGGGCCCGGGG-C

Variant names:

• chr2-42048424-CGGGCCCGGGG-C
• NM_138370.3:c.226_235delGGGCCCGGGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138370.3(PKDCC):​c.226_235delGGGCCCGGGG​(p.Gly76ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PKDCC NM_138370.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 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-CGGGCCCGGGG-C is Pathogenic according to our data. Variant chr2-42048424-CGGGCCCGGGG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2753588.Status of the report is criteria_provided_single_submitter, 1 stars.

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.226_235delGGGCCCGGGG	p.Gly76ArgfsTer9	frameshift	Exon 1 of 7	NP_612379.2	Q504Y2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKDCC	ENST00000294964.6	TSL:1 MANE Select	c.226_235delGGGCCCGGGG	p.Gly76ArgfsTer9	frameshift	Exon 1 of 7	ENSP00000294964.5	Q504Y2
	PKDCC	ENST00000914294.1		c.226_235delGGGCCCGGGG	p.Gly76ArgfsTer9	frameshift	Exon 1 of 7	ENSP00000584353.1
	PKDCC	ENST00000953637.1		c.226_235delGGGCCCGGGG	p.Gly76ArgfsTer9	frameshift	Exon 1 of 7	ENSP00000623696.1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-42275564;