rs1555449461

Variant names:

• chr16-2100177-ACCTCCTTCTCCACCAGGCCCCCGTTGG-A
• rs1555449461
• NM_001009944.3:c.9674_9700delCCAACGGGGGCCTGGTGGAGAAGGAGG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_001009944.3(PKD1):​c.9674_9700delCCAACGGGGGCCTGGTGGAGAAGGAGG​(p.Ala3225_Glu3233del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD1 NM_001009944.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.41

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain PLAT (size 115) in uniprot entity PKD1_HUMAN there are 30 pathogenic changes around while only 9 benign (77%) in NM_001009944.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001009944.3.
• PP5: Variant 16-2100177-ACCTCCTTCTCCACCAGGCCCCCGTTGG-A is Pathogenic according to our data. Variant chr16-2100177-ACCTCCTTCTCCACCAGGCCCCCGTTGG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448028.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr16-2100177-ACCTCCTTCTCCACCAGGCCCCCGTTGG-A is described in Lovd as [Pathogenic]. Variant chr16-2100177-ACCTCCTTCTCCACCAGGCCCCCGTTGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9674_9700delCCAACGGGGGCCTGGTGGAGAAGGAGG	p.Ala3225_Glu3233del	disruptive_inframe_deletion	Exon 28 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9674_9700delCCAACGGGGGCCTGGTGGAGAAGGAGG	p.Ala3225_Glu3233del	disruptive_inframe_deletion	Exon 28 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:1

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 14, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555449461; hg19: chr16-2150178;