rs761532715

Variant names:

• chr2-42053250-C-A
• rs761532715
• NM_138370.3:c.651C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-42053250-C-A
• chr2-42053250-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138370.3(PKDCC):​c.651C>A​(p.Tyr217*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKDCC NM_138370.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.23

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-42053250-C-A is Pathogenic according to our data. Variant chr2-42053250-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 521769.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKDCC	NM_138370.3	c.651C>A	p.Tyr217*	stop_gained	Exon 2 of 7	ENST00000294964.6	NP_612379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKDCC	ENST00000294964.6	c.651C>A	p.Tyr217*	stop_gained	Exon 2 of 7	1	NM_138370.3	ENSP00000294964.5
PKDCC	ENST00000401498.6	n.509C>A		non_coding_transcript_exon_variant	Exon 3 of 8	5		ENSP00000385220.2
PKDCC	ENST00000485578.1	n.272C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
PKDCC	ENST00000492861.1	n.77C>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1418560 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 705750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.651C>A (p.Y217*) alteration, located in coding exon 2 of the PKDCC gene, consists of a C to A substitution at nucleotide position 651. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 217. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/248834) total alleles studied. The highest observed frequency was 0.019% (4/21292) of European (Finnish) alleles. Based on the available evidence, this alteration is classified as pathogenic. -

Rhizomelic limb shortening with dysmorphic features Pathogenic:1

Mar 20, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
Vest4		0.30
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761532715; hg19: chr2-42280390;