NM_001009944.3:c.3372C>T

Variant names:

• chr16-2111795-G-A
• rs75510884
• NM_001009944.3:c.3372C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.3372C>T​(p.Ala1124Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0994 in 1,608,608 control chromosomes in the GnomAD database, including 9,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1985 hom., cov: 33)
  • Exomes 𝑓: 0.095 (7751 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.171
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-2111795-G-A is Benign according to our data. Variant chr16-2111795-G-A is described in ClinVar as Benign. ClinVar VariationId is 256949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.171 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.26 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.3372C>T	p.Ala1124Ala	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.3372C>T	p.Ala1124Ala	synonymous	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.3372C>T	p.Ala1124Ala	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.3372C>T	p.Ala1124Ala	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-3437C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21201 AN: 152046 Hom.: 1982 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0978

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.0888 AC: 21441 AN: 241434 AF XY: 0.0847

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.0975

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0952 AC: 138674 AN: 1456444 Hom.: 7751 Cov.: 36 AF XY: 0.0933 AC XY: 67559 AN XY: 724404

African (AFR) AF: 0.274 AC: 9132 AN: 33372

American (AMR) AF: 0.0773 AC: 3441 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3720 AN: 26064

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39654

South Asian (SAS) AF: 0.0317 AC: 2727 AN: 85936

European-Finnish (FIN) AF: 0.0703 AC: 3654 AN: 51974

Middle Eastern (MID) AF: 0.164 AC: 680 AN: 4136

European-Non Finnish (NFE) AF: 0.0982 AC: 109095 AN: 1110708

Other (OTH) AF: 0.104 AC: 6222 AN: 60104

GnomAD4 genome AF: 0.140 AC: 21234 AN: 152164 Hom.: 1985 Cov.: 33 AF XY: 0.134 AC XY: 9968 AN XY: 74412

African (AFR) AF: 0.264 AC: 10944 AN: 41478

American (AMR) AF: 0.111 AC: 1703 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4830

European-Finnish (FIN) AF: 0.0759 AC: 806 AN: 10622

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.0979 AC: 6653 AN: 67986

Other (OTH) AF: 0.145 AC: 307 AN: 2114

Alfa AF: 0.117 Hom.: 443

Bravo AF: 0.151

Asia WGS AF: 0.0300 AC: 107 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.12
DANN	Benign	0.75
PhyloP100		-0.17
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: rs75510884; hg19: chr16-2161796; COSMIC: COSV51917050; COSMIC: COSV51917050;