17-8145000-A-G

Position:

• chr17-8145000-A-G

Variant summary

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

The NM_002616.3(PER1):​c.2219-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,461,254 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: PER1 NM_002616.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001099
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08

Genes affected

PER1 (HGNC:8845): (period circadian regulator 1) This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers. Alternative splicing has been observed in this gene; however, these variants have not been fully described. [provided by RefSeq, Jan 2014]

PER1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-8145000-A-G is Benign according to our data. Variant chr17-8145000-A-G is described in ClinVar as [Benign]. Clinvar id is 710104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1961/152104) while in subpopulation AFR AF= 0.0438 (1814/41446). AF 95% confidence interval is 0.0421. There are 48 homozygotes in gnomad4. There are 936 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER1	NM_002616.3	c.2219-7T>C		splice_region_variant, intron_variant		ENST00000317276.9	NP_002607.2
MIR6883	NR_106943.1	n.72T>C		non_coding_transcript_exon_variant	1/1
MIR6883	unassigned_transcript_2948	n.16T>C		non_coding_transcript_exon_variant	1/1
MIR6883	unassigned_transcript_2949	n.*45T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER1	ENST00000317276.9	c.2219-7T>C		splice_region_variant, intron_variant		1	NM_002616.3	ENSP00000314420.4

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1963 AN: 151986 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00793

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: 0.0000588

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00393 AC: 570 AN: 144866 Hom.: 11 AF XY: 0.00304 AC XY: 237 AN XY: 77892

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000925

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000959

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00114 AC: 1490 AN: 1309150 Hom.: 33 Cov.: 31 AF XY: 0.000981 AC XY: 626 AN XY: 638130

Gnomad4 AFR exome AF: 0.0418

Gnomad4 AMR exome AF: 0.00348

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000347

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.0129 AC: 1961 AN: 152104 Hom.: 48 Cov.: 31 AF XY: 0.0126 AC XY: 936 AN XY: 74364

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.00792

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00679 Hom.: 5

Bravo AF: 0.0148

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.016
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: rs113376788; hg19: chr17-8048318;