NM_138370.3:c.13C>T

Variant names:

• chr2-42048212-C-T
• rs1268143326
• NM_138370.3:c.13C>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.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 1,195,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: PKDCC NM_138370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.33
• 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=0.25350946).

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.13C>T	p.Arg5Trp	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.13C>T	p.Arg5Trp	missense	Exon 1 of 7	ENSP00000294964.5	Q504Y2
	PKDCC	ENST00000914294.1		c.13C>T	p.Arg5Trp	missense	Exon 1 of 7	ENSP00000584353.1
	PKDCC	ENST00000953637.1		c.13C>T	p.Arg5Trp	missense	Exon 1 of 7	ENSP00000623696.1

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 146054 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000667 AC: 7 AN: 1049682 Hom.: 0 Cov.: 31 AF XY: 0.00000785 AC XY: 4 AN XY: 509340

⚠️ 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: 20192

American (AMR) AF: 0.00 AC: 0 AN: 11918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12322

East Asian (EAS) AF: 0.00 AC: 0 AN: 17224

South Asian (SAS) AF: 0.0000267 AC: 1 AN: 37516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2604

European-Non Finnish (NFE) AF: 0.00000673 AC: 6 AN: 891550

Other (OTH) AF: 0.00 AC: 0 AN: 38544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00862235), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000685 AC: 1 AN: 146054 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 71052

African (AFR) AF: 0.00 AC: 0 AN: 40578

American (AMR) AF: 0.00 AC: 0 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4992

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65722

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.33		Loss of disorder (P = 0.003)
MVP		0.69
MPC		1.9
ClinPred		0.66	D
GERP RS		2.9
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.13
gMVP		0.40
Mutation Taster		=81/19	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: rs1268143326; hg19: chr2-42275352;