rs7194935

Variant names:

• chr16-2097356-G-A
• rs7194935
• NM_001009944.3:c.10368C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2097356-G-A
• chr16-2097356-G-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.375
• Publications: 4 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=-0.62).
• 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.

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.10368C>T	p.Ala3456Ala	synonymous	Exon 33 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.10365C>T	p.Ala3455Ala	synonymous	Exon 33 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.10368C>T	p.Ala3456Ala	synonymous	Exon 33 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.10365C>T	p.Ala3455Ala	synonymous	Exon 33 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000487932.5	TSL:5	n.*1561C>T		non_coding_transcript_exon	Exon 20 of 30	ENSP00000457132.1	H3BTE0

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4437 AN: 152184 Hom.: 238 Cov.: 33

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

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.: 33 AF XY: 0.00275 AC XY: 1998 AN XY: 726380

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: 0 AN: 39696

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51782

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5766

European-Non Finnish (NFE) AF: 0.000335 AC: 373 AN: 1111930

Other (OTH) AF: 0.00704 AC: 425 AN: 60342

GnomAD4 genome AF: 0.0293 AC: 4460 AN: 152302 Hom.: 240 Cov.: 33 AF XY: 0.0290 AC XY: 2160 AN XY: 74468

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: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68018

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0201 Hom.: 67

Bravo AF: 0.0328

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

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	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	-0.62
CADD	Benign	0.73
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)

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: rs7194935; hg19: chr16-2147357;