rs1667901626

Variant names:

• chr2-42048294-C-T
• rs1667901626
• NM_138370.3:c.95C>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.95C>T​(p.Pro32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000538 in 1,115,936 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.0000054 (1 hom.)
• Consequence: PKDCC NM_138370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

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=0.087732434).

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.95C>T	p.Pro32Leu	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.95C>T	p.Pro32Leu	missense	Exon 1 of 7	ENSP00000294964.5	Q504Y2
	PKDCC	ENST00000914294.1		c.95C>T	p.Pro32Leu	missense	Exon 1 of 7	ENSP00000584353.1
	PKDCC	ENST00000953637.1		c.95C>T	p.Pro32Leu	missense	Exon 1 of 7	ENSP00000623696.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000538 AC: 6 AN: 1115936 Hom.: 1 Cov.: 31 AF XY: 0.00000367 AC XY: 2 AN XY: 544370

African (AFR) AF: 0.00 AC: 0 AN: 21678

American (AMR) AF: 0.00 AC: 0 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14798

East Asian (EAS) AF: 0.00 AC: 0 AN: 23090

South Asian (SAS) AF: 0.0000233 AC: 1 AN: 42970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2932

European-Non Finnish (NFE) AF: 0.00000535 AC: 5 AN: 934398

Other (OTH) AF: 0.00 AC: 0 AN: 42668

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.051
Sift	Benign	0.16	T
Sift4G	Uncertain	0.053	T
Polyphen		0.59	P
Vest4		0.058
MutPred		0.17		Loss of glycosylation at P32 (P = 0.0078)
MVP		0.66
MPC		1.9
ClinPred		0.14	T
GERP RS		2.4
PromoterAI		0.029	Neutral
Varity_R		0.038
gMVP		0.28
Mutation Taster		=80/20	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: rs1667901626; hg19: chr2-42275434;