rs62406032

Variant names:

• chr6-52046107-T-C
• rs62406032
• NM_138694.4:c.2489A>G

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.2489A>G​(p.Asn830Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 1,612,894 control chromosomes in the GnomAD database, including 4,189 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. N830K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (294 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3895 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.983
• Publications: 32 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, 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=0.0015713573).
• BP6: Variant 6-52046107-T-C is Benign according to our data. Variant chr6-52046107-T-C is described in ClinVar as Benign. ClinVar VariationId is 96391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.2489A>G	p.Asn830Ser	missense	Exon 24 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.2489A>G	p.Asn830Ser	missense	Exon 24 of 61	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.2489A>G	p.Asn830Ser	missense	Exon 24 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.2489A>G	p.Asn830Ser	missense	Exon 24 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8037 AN: 152140 Hom.: 294 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0992

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0668

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0666 AC: 16727 AN: 251260 AF XY: 0.0699

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0911

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0698 AC: 101954 AN: 1460636 Hom.: 3895 Cov.: 31 AF XY: 0.0706 AC XY: 51308 AN XY: 726658

African (AFR) AF: 0.00995 AC: 333 AN: 33454

American (AMR) AF: 0.0333 AC: 1488 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 1303 AN: 26118

East Asian (EAS) AF: 0.117 AC: 4634 AN: 39686

South Asian (SAS) AF: 0.0970 AC: 8367 AN: 86238

European-Finnish (FIN) AF: 0.0913 AC: 4876 AN: 53418

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5762

European-Non Finnish (NFE) AF: 0.0692 AC: 76877 AN: 1110890

Other (OTH) AF: 0.0650 AC: 3922 AN: 60348

GnomAD4 genome AF: 0.0528 AC: 8035 AN: 152258 Hom.: 294 Cov.: 32 AF XY: 0.0550 AC XY: 4098 AN XY: 74448

African (AFR) AF: 0.0120 AC: 498 AN: 41564

American (AMR) AF: 0.0394 AC: 602 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3468

East Asian (EAS) AF: 0.108 AC: 560 AN: 5180

South Asian (SAS) AF: 0.0998 AC: 481 AN: 4822

European-Finnish (FIN) AF: 0.0992 AC: 1052 AN: 10604

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0668 AC: 4542 AN: 68014

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0627 Hom.: 775

Bravo AF: 0.0459

TwinsUK AF: 0.0766 AC: 284

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.0687 AC: 591

ExAC AF: 0.0678 AC: 8237

Asia WGS AF: 0.106 AC: 367 AN: 3478

EpiCase AF: 0.0612

EpiControl AF: 0.0639

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Autosomal recessive polycystic kidney disease (6)
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.98
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.068	T
Polyphen		0.024	B
Vest4		0.043
MPC		0.054
ClinPred		0.0049	T
GERP RS		3.7
Varity_R		0.058
gMVP		0.41
Mutation Taster		=98/2	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: rs62406032; hg19: chr6-51910905; COSMIC: COSV61866420;