2-42048464-G-C

Position:

chr2-42048464-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_138370.3(PKDCC):c.265G>C(p.Asp89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 1,070,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D89D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

PKDCC
NM_138370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11200985).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000232 (34/146596) while in subpopulation AMR AF= 0.00196 (29/14808). AF 95% confidence interval is 0.0014. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKDCC	NM_138370.3 linkuse as main transcript	c.265G>C	p.Asp89His	missense_variant	1/7	ENST00000294964.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKDCC	ENST00000294964.6 linkuse as main transcript	c.265G>C	p.Asp89His	missense_variant	1/7	1	NM_138370.3	P1
PKDCC	ENST00000401498.6 linkuse as main transcript	c.198+67G>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

146488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000982

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

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:

0.00

Gnomad OTH

AF:

0.000493

GnomAD4 exome

AF:

0.00000108

AC:

AN:

923868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

437218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000297

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

AF:

0.000232

AC:

AN:

146596

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

AN XY:

71426

show subpopulations

Gnomad4 AFR

AF:

0.0000979

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000488

Bravo

AF:

0.000261

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.265G>C (p.D89H) alteration is located in exon 1 (coding exon 1) of the PKDCC gene. This alteration results from a G to C substitution at nucleotide position 265, causing the aspartic acid (D) at amino acid position 89 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 89 of the PKDCC protein (p.Asp89His). This variant is present in population databases (no rsID available, gnomAD 0.3%). This variant has not been reported in the literature in individuals affected with PKDCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1354847). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.073

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.61

M_CAP

Benign

0.045

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.3

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.78

Vest4

0.10

MutPred

0.21

Gain of MoRF binding (P = 0.0492);

MVP

0.65

MPC

2.2

ClinPred

0.47

GERP RS

1.9

Varity_R

0.32

gMVP

0.44

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over