NM_001009944.3:c.4665A>C

Variant names:

• chr16-2110502-T-G
• rs71385734
• NM_001009944.3:c.4665A>C

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.4665A>C​(p.Ala1555Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,016 control chromosomes in the GnomAD database, including 30,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1555A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (6671 hom., cov: 34)
  • Exomes 𝑓: 0.17 (23692 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.74
• Publications: 22 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=-0.57).
• BP6: Variant 16-2110502-T-G is Benign according to our data. Variant chr16-2110502-T-G is described in ClinVar as Benign. ClinVar VariationId is 256968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 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.4665A>C	p.Ala1555Ala	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.4665A>C	p.Ala1555Ala	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.4665A>C	p.Ala1555Ala	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.4665A>C	p.Ala1555Ala	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-2144A>C		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38340 AN: 152084 Hom.: 6649 Cov.: 34

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0882

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.246

GnomAD2 exomes AF: 0.164 AC: 40642 AN: 248566 AF XY: 0.158

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.168 AC: 244989 AN: 1459814 Hom.: 23692 Cov.: 37 AF XY: 0.165 AC XY: 119809 AN XY: 726224

African (AFR) AF: 0.503 AC: 16824 AN: 33454

American (AMR) AF: 0.121 AC: 5397 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6237 AN: 26118

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39698

South Asian (SAS) AF: 0.0900 AC: 7763 AN: 86232

European-Finnish (FIN) AF: 0.183 AC: 9517 AN: 51874

Middle Eastern (MID) AF: 0.236 AC: 1329 AN: 5622

European-Non Finnish (NFE) AF: 0.168 AC: 187024 AN: 1111770

Other (OTH) AF: 0.180 AC: 10887 AN: 60336

GnomAD4 genome AF: 0.252 AC: 38409 AN: 152202 Hom.: 6671 Cov.: 34 AF XY: 0.248 AC XY: 18421 AN XY: 74416

African (AFR) AF: 0.489 AC: 20294 AN: 41508

American (AMR) AF: 0.185 AC: 2835 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5190

South Asian (SAS) AF: 0.0878 AC: 424 AN: 4828

European-Finnish (FIN) AF: 0.191 AC: 2032 AN: 10612

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11293 AN: 67980

Other (OTH) AF: 0.244 AC: 515 AN: 2112

Alfa AF: 0.154 Hom.: 696

Bravo AF: 0.264

Asia WGS AF: 0.0770 AC: 269 AN: 3478

EpiCase AF: 0.179

EpiControl AF: 0.177

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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	-0.57
CADD	Benign	3.8
DANN	Benign	0.67
PhyloP100		1.7
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: rs71385734; hg19: chr16-2160503; COSMIC: COSV51916428; COSMIC: COSV51916428;