rs528302390

Variant names:

• chr7-47831213-TCA-T
• rs528302390
• NM_138295.5:c.6473+2_6473+3delTG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000289672.7(PKD1L1):​c.6473+2_6473+3delTG variant causes a splice donor, splice region, intron change. The variant allele was found at a frequency of 0.000861 in 1,611,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: PKD1L1 ENST00000289672.7 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.86
• Publications: 10 publications found

Genes affected

PKD1L1 (HGNC:18053): (polycystin 1 like 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family containing 11 transmembrane domains, a receptor for egg jelly (REJ) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. The encoded protein may play a role in the male reproductive system. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

PKD1L1 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 8, autosomal

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• situs inversus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 7-47831213-TCA-T is Pathogenic according to our data. Variant chr7-47831213-TCA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 235796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000289672.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1L1	NM_138295.5	MANE Select	c.6473+2_6473+3delTG		splice_donor splice_region intron	N/A	NP_612152.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1L1	ENST00000289672.7	TSL:1 MANE Select	c.6473+2_6473+3delTG		splice_donor splice_region intron	N/A	ENSP00000289672.2
	PKD1L1	ENST00000690269.1		c.6473+2_6473+3delTG		splice_donor splice_region intron	N/A	ENSP00000510743.1
	PKD1L1	ENST00000685709.1		c.6305+2_6305+3delTG		splice_donor splice_region intron	N/A	ENSP00000509540.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

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: 0.000955

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000366 AC: 91 AN: 248798 AF XY: 0.000379

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.000407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000718

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000899 AC: 1311 AN: 1459094 Hom.: 0 AF XY: 0.000838 AC XY: 608 AN XY: 725820

African (AFR) AF: 0.000270 AC: 9 AN: 33356

American (AMR) AF: 0.0000456 AC: 2 AN: 43848

Ashkenazi Jewish (ASJ) AF: 0.000386 AC: 10 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00110 AC: 1222 AN: 1111036

Other (OTH) AF: 0.00111 AC: 67 AN: 60222

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74352

African (AFR) AF: 0.000193 AC: 8 AN: 41434

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000955 AC: 65 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000912 Hom.: 0

Bravo AF: 0.000540

EpiCase AF: 0.000873

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Heterotaxy, visceral, 8, autosomal (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	PKD1L1-related disorder (1)
1	-	-	Situs inversus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs528302390; hg19: chr7-47870811; COSMIC: COSV108066478; COSMIC: COSV108066478;