NM_001009944.3:c.4195T>C

Variant names:

• chr16-2110972-A-G
• rs116092985
• NM_001009944.3:c.4195T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.4195T>C​(p.Trp1399Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,597,052 control chromosomes in the GnomAD database, including 6,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. W1399Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.078 (563 hom., cov: 33)
  • Exomes 𝑓: 0.085 (6263 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.237
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042101443).
• BP6: Variant 16-2110972-A-G is Benign according to our data. Variant chr16-2110972-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

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.4195T>C	p.Trp1399Arg	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.4195T>C	p.Trp1399Arg	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.4195T>C	p.Trp1399Arg	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.4195T>C	p.Trp1399Arg	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-2614T>C		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11846 AN: 152206 Hom.: 563 Cov.: 33

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0942

GnomAD2 exomes AF: 0.0650 AC: 15796 AN: 243130 AF XY: 0.0657

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.0850

Gnomad OTH exome AF: 0.0930

GnomAD4 exome AF: 0.0850 AC: 122750 AN: 1444728 Hom.: 6263 Cov.: 36 AF XY: 0.0839 AC XY: 60294 AN XY: 718702

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0468 AC: 1554 AN: 33210

American (AMR) AF: 0.0596 AC: 2648 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3591 AN: 25860

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0301 AC: 2587 AN: 85944

European-Finnish (FIN) AF: 0.0684 AC: 3548 AN: 51884

Middle Eastern (MID) AF: 0.147 AC: 614 AN: 4174

European-Non Finnish (NFE) AF: 0.0937 AC: 103098 AN: 1099796

Other (OTH) AF: 0.0855 AC: 5108 AN: 59766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0778 AC: 11849 AN: 152324 Hom.: 563 Cov.: 33 AF XY: 0.0741 AC XY: 5521 AN XY: 74472

African (AFR) AF: 0.0505 AC: 2098 AN: 41584

American (AMR) AF: 0.0847 AC: 1295 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4828

European-Finnish (FIN) AF: 0.0760 AC: 808 AN: 10626

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0976 AC: 6635 AN: 68014

Other (OTH) AF: 0.0932 AC: 197 AN: 2114

Alfa AF: 0.0814 Hom.: 242

Bravo AF: 0.0795

TwinsUK AF: 0.0963 AC: 357

ALSPAC AF: 0.0929 AC: 358

ExAC AF: 0.0662 AC: 8003

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.9
DANN	Benign	0.44
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.055	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.24
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.091
Sift	Benign	0.36	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.021
MutPred		0.60		Loss of catalytic residue at W1399 (P = 0.0152)
ClinPred		0.0042	T
GERP RS		3.4
Varity_R		0.057
gMVP		0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs116092985; hg19: chr16-2160973; COSMIC: COSV51916806; COSMIC: COSV51916806;