rs377441860

Variant names:

• chr16-2112393-G-A
• rs377441860
• NM_001009944.3:c.3242C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2112393-G-A
• chr16-2112393-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001009944.3(PKD1):​c.3242C>T​(p.Ser1081Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,587,058 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1081P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (6 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.05
• Publications: 3 publications found

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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ENSG00000261240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014880568).
• BP6: Variant 16-2112393-G-A is Benign according to our data. Variant chr16-2112393-G-A is described in ClinVar as Benign. ClinVar VariationId is 433955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000197 (30/152332) while in subpopulation SAS AF = 0.0058 (28/4830). AF 95% confidence interval is 0.00412. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.3242C>T	p.Ser1081Leu	missense	Exon 14 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.3242C>T	p.Ser1081Leu	missense	Exon 14 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.3242C>T	p.Ser1081Leu	missense	Exon 14 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.3242C>T	p.Ser1081Leu	missense	Exon 14 of 46	ENSP00000399501.1
	PKD1	ENST00000483024.1	TSL:5	c.122C>T	p.Ser41Leu	missense	Exon 2 of 5	ENSP00000456670.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000886 AC: 190 AN: 214364 AF XY: 0.00127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000302

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000363 AC: 521 AN: 1434726 Hom.: 6 Cov.: 32 AF XY: 0.000560 AC XY: 400 AN XY: 713868

African (AFR) AF: 0.00 AC: 0 AN: 32222

American (AMR) AF: 0.0000226 AC: 1 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39640

South Asian (SAS) AF: 0.00576 AC: 492 AN: 85422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1105858

Other (OTH) AF: 0.000218 AC: 13 AN: 59754

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000958 AC: 109

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.0
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.031
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.025	D
Polyphen		0.38	B
Vest4		0.21
MutPred		0.51		Loss of sheet (P = 0.007)
MVP		0.58
ClinPred		0.034	T
GERP RS		1.9
PromoterAI		0.011	Neutral
Varity_R		0.067
gMVP		0.30
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs377441860; hg19: chr16-2162394; COSMIC: COSV51922755; COSMIC: COSV51922755;