2-42048398-G-C

Position:

• chr2-42048398-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138370.3(PKDCC):​c.199G>C​(p.Val67Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PKDCC NM_138370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09373021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKDCC	NM_138370.3	c.199G>C	p.Val67Leu	missense_variant	1/7	ENST00000294964.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKDCC	ENST00000294964.6	c.199G>C	p.Val67Leu	missense_variant	1/7	1	NM_138370.3	P1
PKDCC	ENST00000401498.6	c.198+1G>C		splice_donor_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PKDCC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 67 of the PKDCC protein (p.Val67Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.58	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.27	N
REVEL	Benign	0.068
Sift	Uncertain	0.026	D
Sift4G	Benign	0.30	T
Polyphen		0.047	B
Vest4		0.045
MutPred		0.17		Loss of phosphorylation at Y64 (P = 0.1089);
MVP		0.50
MPC		2.8
ClinPred		0.42	T
GERP RS		2.2
Varity_R		0.14
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1048062777; hg19: chr2-42275538;