3-71772503-A-C

Position:

• chr3-71772503-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001126128.2(PROK2):​c.*221T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 496,308 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (8 hom.)
• Consequence: PROK2 NM_001126128.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.12

Genes affected

PROK2 (HGNC:18455): (prokineticin 2) This gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to this gene product were isolated based on homology to snake venom and secretions from frog skin, and have been shown to have diverse functions. Mutations in this gene are associated with Kallmann syndrome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-71772503-A-C is Benign according to our data. Variant chr3-71772503-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1215646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00355 (541/152242) while in subpopulation NFE AF= 0.0051 (347/68024). AF 95% confidence interval is 0.00466. There are 4 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROK2	NM_001126128.2	c.*221T>G		3_prime_UTR_variant	4/4	ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4	c.*221T>G		3_prime_UTR_variant	3/3		NP_068754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619	c.*221T>G		3_prime_UTR_variant	4/4	1	NM_001126128.2	ENSP00000295619.3
PROK2	ENST00000353065	c.*221T>G		3_prime_UTR_variant	3/3	1		ENSP00000295618.3

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152124 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00395 AC: 1359 AN: 344066 Hom.: 8 Cov.: 3 AF XY: 0.00390 AC XY: 703 AN XY: 180394

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.000913

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.00425

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.00355 AC: 541 AN: 152242 Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74452

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00260

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.3
DANN	Benign	0.75

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: rs183366125; hg19: chr3-71821654;