chr2-42048464-G-C

Position:

• chr2-42048464-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.08

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 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	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	c.265G>C	p.Asp89His	missense_variant	1/7	1	NM_138370.3	P1
PKDCC	ENST00000401498.6	c.198+67G>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 34 AN: 146488 Hom.: 0 Cov.: 30

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: 1 AN: 923868 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 437218

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: 34 AN: 146596 Hom.: 0 Cov.: 30 AF XY: 0.000182 AC XY: 13 AN XY: 71426

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

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	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.78	P
Vest4		0.10
MutPred		0.21		Gain of MoRF binding (P = 0.0492);
MVP		0.65
MPC		2.2
ClinPred		0.47	T
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

Other links and lift over

dbSNP: rs1292367097; hg19: chr2-42275604;