rs1405122434

Variant names:

• chr2-42048411-C-T
• rs1405122434
• NM_138370.3:c.212C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138370.3(PKDCC):​c.212C>T​(p.Ser71Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000045 in 999,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: PKDCC NM_138370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.860
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09043625).

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.212C>T	p.Ser71Phe	missense	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.212C>T	p.Ser71Phe	missense	Exon 1 of 7	ENSP00000294964.5	Q504Y2
	PKDCC	ENST00000914294.1		c.212C>T	p.Ser71Phe	missense	Exon 1 of 7	ENSP00000584353.1
	PKDCC	ENST00000953637.1		c.212C>T	p.Ser71Phe	missense	Exon 1 of 7	ENSP00000623696.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000450 AC: 45 AN: 999656 Hom.: 0 Cov.: 31 AF XY: 0.0000419 AC XY: 20 AN XY: 477314

African (AFR) AF: 0.00 AC: 0 AN: 19270

American (AMR) AF: 0.00 AC: 0 AN: 6012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9984

East Asian (EAS) AF: 0.00 AC: 0 AN: 17798

South Asian (SAS) AF: 0.00 AC: 0 AN: 22152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2374

European-Non Finnish (NFE) AF: 0.0000460 AC: 40 AN: 869800

Other (OTH) AF: 0.000137 AC: 5 AN: 36604

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.86
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.069
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.044	D
Polyphen		0.026	B
Vest4		0.087
MutPred		0.14		Loss of phosphorylation at S71 (P = 0.004)
MVP		0.63
MPC		2.1
ClinPred		0.31	T
GERP RS		2.2
PromoterAI		0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.11
gMVP		0.29
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1405122434; hg19: chr2-42275551;