NM_001009944.3:c.12436G>A

Variant names:

• chr16-2090293-C-T
• rs148478410
• NM_001009944.3:c.12436G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.12436G>A​(p.Val4146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,609,992 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0038 (28 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.77
• Publications: 21 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]

MIR1225 (HGNC:33931): (microRNA 1225) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010210127).
• BP6: Variant 16-2090293-C-T is Benign according to our data. Variant chr16-2090293-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00329 (501/152306) while in subpopulation SAS AF = 0.00642 (31/4830). AF 95% confidence interval is 0.00501. There are 3 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.12436G>A	p.Val4146Ile	missense_variant	Exon 45 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12436G>A	p.Val4146Ile	missense_variant	Exon 45 of 46	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.12433G>A	p.Val4145Ile	missense_variant	Exon 45 of 46	1		ENSP00000399501.1
PKD1	ENST00000472577.1	n.464G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2
MIR1225	ENST00000408729.1	n.-9G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152188 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00439 AC: 1076 AN: 244946 AF XY: 0.00484

Gnomad AFR exome AF: 0.000504

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.00287

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00442

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00384 AC: 5592 AN: 1457686 Hom.: 28 Cov.: 34 AF XY: 0.00409 AC XY: 2963 AN XY: 724654

African (AFR) AF: 0.000689 AC: 23 AN: 33398

American (AMR) AF: 0.00283 AC: 126 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 56 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00834 AC: 717 AN: 86000

European-Finnish (FIN) AF: 0.00527 AC: 274 AN: 51964

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5760

European-Non Finnish (NFE) AF: 0.00363 AC: 4025 AN: 1110160

Other (OTH) AF: 0.00448 AC: 270 AN: 60226

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152306 Hom.: 3 Cov.: 34 AF XY: 0.00290 AC XY: 216 AN XY: 74472

African (AFR) AF: 0.000649 AC: 27 AN: 41574

American (AMR) AF: 0.00163 AC: 25 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 67994

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00435 Hom.: 2

Bravo AF: 0.00276

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000911 AC: 4

ESP6500EA AF: 0.00431 AC: 37

ExAC AF: 0.00470 AC: 569

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BS2 -

Mar 16, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22383692, 10200984, 27843768, 27499327, 27401137, 11967008, 31488014) -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.12436G>A (p.Val4146Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 244946 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. c.12436G>A has been observed in individuals affected with Polycystic Kidney Disease without evidence of cosegregation with disease (e.g., Edrees_2016, Carrera_2016, Al-Muhanna_2019). These reports do not provide unequivocal conclusions about association of the variant with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27843768, 27499327, 31488014). ClinVar contains an entry for this variant (Variation ID: 256919). Based on the evidence outlined above, the variant was classified as likely benign. -

Polycystic kidney disease, adult type Benign:2

Feb 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2017

Athena Diagnostics

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Val4146Ile variant was identified in 8 of 1080 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Badenas 1999, Rossetti 2012, Rossetti 2002, Stekrova 2009). The variant was also identified in the following databases: dbSNP (ID: rs148478410) as “With Likely benign allele”, ClinVar (1x, as likely benign by Prevention Genetics), LOVD 3.0 (1x, with unknown effect, 1x as "Probably does not affect function"), ADPKD Mutation Database (as likely neutral). The variant was not identified in the PKD1-LOVD database. The variant was identified in control databases in 1211 of 271698 (5 homozygous) chromosomes at a frequency of 0.004457 in the following populations: African in 11 of 23782 chromosomes (freq. 0.00046), other in 41 of 6358 chromosomes (freq. 0.0064), Latino in 102 of 34238 chromosomes (freq. 0.003), European in 644 of 12418 (2 homozygous) chromosomes (freq. 0.005), Ashkenazi Jewish in 30 of 9890 chromosomes (freq. 0.003), East Asian in 1 of 18826 chromosomes (freq. 0.00005), Finnish in 117 of 25656 chromosomes (freq. 0.0045), and South Asian in 265 of 30530 (3 homozygous) chromosomes (freq. 0.0086), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic PKD1 variant (c.7864-1G>T) was identified in 1 individual with ADPKD in our laboratory, increasing the likelihood that p.Val4146Ile variant does not have clinical significance. The p.Val4146 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.072
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.034	D;D
Polyphen		0.97	D;D
Vest4		0.81
MVP		0.78
ClinPred		0.018	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.26
Mutation Taster		=91/9	polymorphism

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: rs148478410; hg19: chr16-2140294; COSMIC: COSV99238895; COSMIC: COSV99238895;