NM_001009944.3:c.10368C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001009944.3(PKD1):c.10368C>T(p.Ala3456Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 1,612,382 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 240 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 162 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.375

Publications

4 publications found

Variant links:

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: ClinGen, Orphanet
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

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 16-2097356-G-A is Benign according to our data. Variant chr16-2097356-G-A is described in ClinVar as Benign. ClinVar VariationId is 256889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.375 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.10368C>T	p.Ala3456Ala	synonymous_variant	Exon 33 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKD1	ENST00000262304.9 link	c.10368C>T	p.Ala3456Ala	synonymous_variant	Exon 33 of 46	1	NM_001009944.3	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5 link	c.10365C>T	p.Ala3455Ala	synonymous_variant	Exon 33 of 46	1		ENSP00000399501.1	P98161-3
PKD1	ENST00000487932.5 link	n.*1561C>T		non_coding_transcript_exon_variant	Exon 20 of 30	5		ENSP00000457132.1	H3BTE0
PKD1	ENST00000487932.5 link	n.*1561C>T		3_prime_UTR_variant	Exon 20 of 30	5		ENSP00000457132.1	H3BTE0

Frequencies

GnomAD3 genomes

AF:

0.0292

AC:

4437

AN:

152184

Hom.:

238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.00770

AC:

1903

AN:

247168

AF XY:

0.00572

show subpopulations

Gnomad AFR exome

AF:

0.0990

Gnomad AMR exome

AF:

0.00566

Gnomad ASJ exome

AF:

0.00543

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.00578

GnomAD4 exome

AF:

0.00316

AC:

4616

AN:

1460080

Hom.:

162

Cov.:

AF XY:

0.00275

AC XY:

1998

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.0991

AC:

3316

AN:

33476

American (AMR)

AF:

0.00608

AC:

272

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000197

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51782

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000335

AC:

373

AN:

1111930

Other (OTH)

AF:

0.00704

AC:

425

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

272

544

816

1088

1360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0293

AC:

4460

AN:

152302

Hom.:

240

Cov.:

AF XY:

0.0290

AC XY:

2160

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.101

AC:

4178

AN:

41564

American (AMR)

AF:

0.0112

AC:

172

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68018

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0328

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22008521) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Polycystic kidney disease, adult type

Benign:1

Jan 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Ala3456Ala variant was identified in 4 of 534 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Rossetti 2012). These studies have both identified the variant as a polymorphism. The p.Ala3456Ala variant was identified in the dbSNP (ID: rs7194935) with â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹ with a minor allele frequency of 0.03 (152 of 5000 chromosomes in 1000 Genome Project). In the NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 5 of 8594 alleles (frequency: 0.0005) in the European Americans and 423 of 4392 alleles in African Americans (Frequency: 0.1). The variant was identified in the Exome Aggregation Consortium database (August 08, 2016) in 1034 of 114508 chromosomes (frequency: 0.009 with 45 homozygotes) in the following populations: African in 933of 9530 chromosomes (frequency: 0.1), Latino in 53 of 11138 chromosomes (frequency: 0.005), European (Non-Finnish) in 40 of 62920 chromosomes (frequency: 0.0006), South Asian in 3 of 16084 chromosomes (frequency: 0.0002) and Other in 5 of 820 chromosomes (frequency 0.006) but was not seen in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. The p.Ala3456Ala variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.73

(source)

DANN

Benign

0.76

PhyloP100

-0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over