chr16-2094175-G-A

Variant names:

• chr16-2094175-G-A
• rs34197769
• NM_001009944.3:c.10535C>T

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.10535C>T​(p.Ala3512Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,603,254 control chromosomes in the GnomAD database, including 5,443 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A3512A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.091 (736 hom., cov: 33)
  • Exomes 𝑓: 0.076 (4707 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.536
• Publications: 35 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002803743).
• BP6: Variant 16-2094175-G-A is Benign according to our data. Variant chr16-2094175-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 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.10535C>T	p.Ala3512Val	missense	Exon 35 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.10532C>T	p.Ala3511Val	missense	Exon 35 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.304-546G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.10535C>T	p.Ala3512Val	missense	Exon 35 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.10532C>T	p.Ala3511Val	missense	Exon 35 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000487932.5	TSL:5	n.*1728C>T		non_coding_transcript_exon	Exon 22 of 30	ENSP00000457132.1	H3BTE0

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13762 AN: 152136 Hom.: 735 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0979

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.0735

GnomAD2 exomes AF: 0.0726 AC: 16961 AN: 233670 AF XY: 0.0722

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.0811

Gnomad OTH exome AF: 0.0742

GnomAD4 exome AF: 0.0765 AC: 110966 AN: 1451002 Hom.: 4707 Cov.: 30 AF XY: 0.0754 AC XY: 54426 AN XY: 721564

African (AFR) AF: 0.124 AC: 4118 AN: 33304

American (AMR) AF: 0.0361 AC: 1595 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2831 AN: 25938

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39582

South Asian (SAS) AF: 0.0443 AC: 3768 AN: 85060

European-Finnish (FIN) AF: 0.144 AC: 7422 AN: 51508

Middle Eastern (MID) AF: 0.0650 AC: 374 AN: 5758

European-Non Finnish (NFE) AF: 0.0781 AC: 86371 AN: 1105660

Other (OTH) AF: 0.0747 AC: 4478 AN: 59984

GnomAD4 genome AF: 0.0905 AC: 13779 AN: 152252 Hom.: 736 Cov.: 33 AF XY: 0.0927 AC XY: 6900 AN XY: 74424

African (AFR) AF: 0.129 AC: 5353 AN: 41542

American (AMR) AF: 0.0583 AC: 892 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 340 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0429 AC: 207 AN: 4828

European-Finnish (FIN) AF: 0.145 AC: 1542 AN: 10600

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0774 AC: 5261 AN: 68012

Other (OTH) AF: 0.0728 AC: 154 AN: 2116

Alfa AF: 0.0801 Hom.: 894

Bravo AF: 0.0843

TwinsUK AF: 0.0836 AC: 310

ALSPAC AF: 0.0794 AC: 306

ESP6500AA AF: 0.125 AC: 547

ESP6500EA AF: 0.0816 AC: 701

ExAC AF: 0.0728 AC: 8774

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.74
DANN	Benign	0.43
DEOGEN2	Benign	0.13	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.54
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	0.34	T
Polyphen		0.23	B
Vest4		0.026
ClinPred		0.012	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.22
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34197769; hg19: chr16-2144176; COSMIC: COSV51916403; COSMIC: COSV51916403;