rs144137200

Variant names:

• chr16-2109556-C-T
• rs144137200
• NM_001009944.3:c.5611G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2109556-C-T
• chr16-2109556-C-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.5611G>A​(p.Ala1871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,611,596 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1871G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (54 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.33
• Publications: 13 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: Orphanet, ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0155184865).
• BP6: Variant 16-2109556-C-T is Benign according to our data. Variant chr16-2109556-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00434 (661/152352) while in subpopulation NFE AF = 0.00731 (497/68024). AF 95% confidence interval is 0.00678. There are 1 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 54 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.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.5611G>A	p.Ala1871Thr	missense	Exon 15 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.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-1198G>A		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00731

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00425 AC: 1044 AN: 245780 AF XY: 0.00449

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00466

GnomAD4 exome AF: 0.00671 AC: 9789 AN: 1459244 Hom.: 54 Cov.: 34 AF XY: 0.00663 AC XY: 4810 AN XY: 725874

African (AFR) AF: 0.000926 AC: 31 AN: 33460

American (AMR) AF: 0.00249 AC: 111 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.00598 AC: 515 AN: 86100

European-Finnish (FIN) AF: 0.00161 AC: 84 AN: 52014

Middle Eastern (MID) AF: 0.00255 AC: 14 AN: 5490

European-Non Finnish (NFE) AF: 0.00782 AC: 8692 AN: 1111496

Other (OTH) AF: 0.00561 AC: 338 AN: 60280

GnomAD4 genome AF: 0.00434 AC: 661 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00391 AC XY: 291 AN XY: 74508

African (AFR) AF: 0.00149 AC: 62 AN: 41586

American (AMR) AF: 0.00353 AC: 54 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00731 AC: 497 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00370 Hom.: 2

Bravo AF: 0.00479

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00572 AC: 49

ExAC AF: 0.00411 AC: 495

EpiCase AF: 0.00780

EpiControl AF: 0.00719

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.027
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.22
MVP		0.92
ClinPred		0.015	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.39
Mutation Taster		=55/45	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: rs144137200; hg19: chr16-2159557; COSMIC: COSV99239466; COSMIC: COSV99239466;