rs9936785

Variant names:

• chr16-2105425-T-C
• rs9936785
• NM_001009944.3:c.7913A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.7913A>G​(p.His2638Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,477,104 control chromosomes in the GnomAD database, including 8,441 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4065 hom., cov: 32)
  • Exomes 𝑓: 0.041 (4376 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.35
• Publications: 15 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010522425).
• BP6: Variant 16-2105425-T-C is Benign according to our data. Variant chr16-2105425-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 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.7913A>G	p.His2638Arg	missense	Exon 21 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.7913A>G	p.His2638Arg	missense	Exon 21 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.7913A>G	p.His2638Arg	missense	Exon 21 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.7913A>G	p.His2638Arg	missense	Exon 21 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000415938.7	TSL:5	n.1158A>G		non_coding_transcript_exon	Exon 7 of 17

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27423 AN: 151594 Hom.: 4044 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.0440 AC: 9388 AN: 213374 AF XY: 0.0383

Gnomad AFR exome AF: 0.297

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.0559

Gnomad EAS exome AF: 0.00240

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0411 AC: 54510 AN: 1325394 Hom.: 4376 Cov.: 33 AF XY: 0.0405 AC XY: 26842 AN XY: 663000

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.264 AC: 6399 AN: 24222

American (AMR) AF: 0.0501 AC: 2158 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 2304 AN: 24582

East Asian (EAS) AF: 0.00613 AC: 243 AN: 39628

South Asian (SAS) AF: 0.0189 AC: 1609 AN: 85012

European-Finnish (FIN) AF: 0.0551 AC: 2067 AN: 37524

Middle Eastern (MID) AF: 0.103 AC: 391 AN: 3778

European-Non Finnish (NFE) AF: 0.0352 AC: 35649 AN: 1011700

Other (OTH) AF: 0.0661 AC: 3690 AN: 55852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.181 AC: 27486 AN: 151710 Hom.: 4065 Cov.: 32 AF XY: 0.174 AC XY: 12879 AN XY: 74150

African (AFR) AF: 0.406 AC: 16730 AN: 41226

American (AMR) AF: 0.130 AC: 1983 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3464

East Asian (EAS) AF: 0.00349 AC: 18 AN: 5162

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4828

European-Finnish (FIN) AF: 0.0759 AC: 805 AN: 10604

Middle Eastern (MID) AF: 0.190 AC: 55 AN: 290

European-Non Finnish (NFE) AF: 0.0992 AC: 6729 AN: 67850

Other (OTH) AF: 0.177 AC: 372 AN: 2104

Alfa AF: 0.133 Hom.: 440

Bravo AF: 0.199

ExAC AF: 0.0483 AC: 5488

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.35
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.10
Sift	Benign	0.37	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.044
ClinPred		0.0044	T
GERP RS		2.5
PromoterAI		-0.0076	Neutral
Varity_R		0.040
gMVP		0.30
Mutation Taster		=99/1	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: rs9936785; hg19: chr16-2155426; COSMIC: COSV51919516; COSMIC: COSV51919516;