chr2-42048424-C-CG

Variant names:

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

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.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 (★). Synonymous variant affecting the same amino acid position (i.e. P77P) has been classified as Likely benign. 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
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

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-C-CG is Pathogenic according to our data. Variant chr2-42048424-C-CG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1803946.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.228dupG	p.Pro77AlafsTer95	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.228dupG	p.Pro77AlafsTer95	frameshift	Exon 1 of 7	ENSP00000294964.5	Q504Y2
	PKDCC	ENST00000914294.1		c.228dupG	p.Pro77AlafsTer95	frameshift	Exon 1 of 7	ENSP00000584353.1
	PKDCC	ENST00000953637.1		c.228dupG	p.Pro77AlafsTer95	frameshift	Exon 1 of 7	ENSP00000623696.1

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

African (AFR) AF: 0.00 AC: 0 AN: 18416

American (AMR) AF: 0.00 AC: 0 AN: 5332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8930

East Asian (EAS) AF: 0.00 AC: 0 AN: 15316

South Asian (SAS) AF: 0.0000460 AC: 1 AN: 21736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 853486

Other (OTH) AF: 0.00 AC: 0 AN: 34794

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rhizomelic limb shortening with dysmorphic features (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26

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

Other links and lift over

hg19: chr2-42275564;