NM_138295.5:c.8103C>A

Variant names:

• chr7-47800739-G-T
• rs1312358074
• NM_138295.5:c.8103C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138295.5(PKD1L1):​c.8103C>A​(p.Cys2701*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD1L1 NM_138295.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.22

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-AS1 (HGNC:21911): (PKD1L1 antisense RNA 1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-47800739-G-T is Pathogenic according to our data. Variant chr7-47800739-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2066496.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1L1	NM_138295.5	c.8103C>A	p.Cys2701*	stop_gained	Exon 54 of 57	ENST00000289672.7	NP_612152.1
PKD1L1	XM_017011798.3	c.8280C>A	p.Cys2760*	stop_gained	Exon 55 of 59		XP_016867287.1
PKD1L1-AS1	NR_161268.1	n.153+5296G>T		intron_variant	Intron 1 of 2
PKD1L1-AS1	NR_161269.1	n.153+5296G>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1L1	ENST00000289672.7	c.8103C>A	p.Cys2701*	stop_gained	Exon 54 of 57	1	NM_138295.5	ENSP00000289672.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys2701*) in the PKD1L1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD1L1 are known to be pathogenic (PMID: 27616478). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKD1L1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Benign	0.94
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0019	N
Vest4		0.090
GERP RS		-8.4

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: rs1312358074; hg19: chr7-47840337; COSMIC: COSV51843919;