rs9296669

Variant names:

• chr6-52026025-G-A
• rs9296669
• NM_138694.4:c.3785C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.3785C>T​(p.Ala1262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,692 control chromosomes in the GnomAD database, including 208,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1262P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.41 (15058 hom., cov: 31)
  • Exomes 𝑓: 0.51 (193271 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.314
• Publications: 44 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.2064343E-5).
• BP6: Variant 6-52026025-G-A is Benign according to our data. Variant chr6-52026025-G-A is described in ClinVar as Benign. ClinVar VariationId is 96399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. 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
	PKHD1	NM_138694.4	MANE Select	c.3785C>T	p.Ala1262Val	missense	Exon 32 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.3785C>T	p.Ala1262Val	missense	Exon 32 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.3785C>T	p.Ala1262Val	missense	Exon 32 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.3785C>T	p.Ala1262Val	missense	Exon 32 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62670 AN: 151922 Hom.: 15058 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.436

GnomAD2 exomes AF: 0.479 AC: 119919 AN: 250462 AF XY: 0.474

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.507

GnomAD4 exome AF: 0.507 AC: 740864 AN: 1461652 Hom.: 193271 Cov.: 58 AF XY: 0.504 AC XY: 366300 AN XY: 727134

African (AFR) AF: 0.144 AC: 4816 AN: 33478

American (AMR) AF: 0.631 AC: 28228 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 12634 AN: 26136

East Asian (EAS) AF: 0.327 AC: 12973 AN: 39698

South Asian (SAS) AF: 0.363 AC: 31351 AN: 86258

European-Finnish (FIN) AF: 0.500 AC: 26652 AN: 53330

Middle Eastern (MID) AF: 0.419 AC: 2415 AN: 5766

European-Non Finnish (NFE) AF: 0.533 AC: 592670 AN: 1111878

Other (OTH) AF: 0.482 AC: 29125 AN: 60392

GnomAD4 genome AF: 0.412 AC: 62671 AN: 152040 Hom.: 15058 Cov.: 31 AF XY: 0.409 AC XY: 30424 AN XY: 74330

African (AFR) AF: 0.158 AC: 6533 AN: 41478

American (AMR) AF: 0.558 AC: 8523 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1686 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1819 AN: 5168

South Asian (SAS) AF: 0.353 AC: 1698 AN: 4816

European-Finnish (FIN) AF: 0.472 AC: 4987 AN: 10558

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35975 AN: 67968

Other (OTH) AF: 0.433 AC: 911 AN: 2106

Alfa AF: 0.485 Hom.: 64593

Bravo AF: 0.409

TwinsUK AF: 0.533 AC: 1976

ALSPAC AF: 0.517 AC: 1993

ESP6500AA AF: 0.150 AC: 660

ESP6500EA AF: 0.517 AC: 4443

ExAC AF: 0.468 AC: 56845

Asia WGS AF: 0.325 AC: 1133 AN: 3478

EpiCase AF: 0.523

EpiControl AF: 0.517

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	3	not specified (3)
-	-	2	Polycystic kidney disease 4 (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.098
DANN	Benign	0.90
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.26	N
PhyloP100		0.31
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.15
Sift	Benign	0.71	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.060
ClinPred		0.0053	T
GERP RS		-1.4
Varity_R		0.020
gMVP		0.20
Mutation Taster		=96/4	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: rs9296669; hg19: chr6-51890823; COSMIC: COSV61882869;