rs2103921770

Variant names:

• chr2-42048296-C-A
• rs2103921770
• NM_138370.3:c.97C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-42048296-C-A
• chr2-42048296-C-G

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.97C>A​(p.Pro33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000898 in 1,114,136 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: 9.0e-7 (0 hom.)
• Consequence: PKDCC NM_138370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.465
• 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=0.11520293).

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.97C>A	p.Pro33Thr	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.97C>A	p.Pro33Thr	missense	Exon 1 of 7	ENSP00000294964.5	Q504Y2
	PKDCC	ENST00000914294.1		c.97C>A	p.Pro33Thr	missense	Exon 1 of 7	ENSP00000584353.1
	PKDCC	ENST00000953637.1		c.97C>A	p.Pro33Thr	missense	Exon 1 of 7	ENSP00000623696.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.98e-7 AC: 1 AN: 1114136 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 543214

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21656

American (AMR) AF: 0.00 AC: 0 AN: 10322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14654

East Asian (EAS) AF: 0.00 AC: 0 AN: 23108

South Asian (SAS) AF: 0.00 AC: 0 AN: 42428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2922

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 933580

Other (OTH) AF: 0.00 AC: 0 AN: 42594

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.47
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.11	T
Polyphen		0.59	P
Vest4		0.074
MutPred		0.15		Gain of phosphorylation at P33 (P = 0.0094)
MVP		0.67
MPC		2.0
ClinPred		0.14	T
GERP RS		2.4
PromoterAI		0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.31
Mutation Taster		=82/18	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: rs2103921770; hg19: chr2-42275436;