rs201753421

Variant names:

• chr6-52043720-C-T
• rs201753421
• NM_138694.4:c.2726G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.2726G>A​(p.Arg909Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,258 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R909R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (7 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.687
• Publications: 3 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 -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_138694.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009226233).
• BP6: Variant 6-52043720-C-T is Benign according to our data. Variant chr6-52043720-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215967.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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.2726G>A	p.Arg909Gln	missense	Exon 26 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.2726G>A	p.Arg909Gln	missense	Exon 26 of 61	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.2726G>A	p.Arg909Gln	missense	Exon 26 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.2726G>A	p.Arg909Gln	missense	Exon 26 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000788 AC: 198 AN: 251180 AF XY: 0.00104

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000359 AC: 525 AN: 1460950 Hom.: 7 Cov.: 30 AF XY: 0.000519 AC XY: 377 AN XY: 726822

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.00553 AC: 477 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111250

Other (OTH) AF: 0.000414 AC: 25 AN: 60362

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74474

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive polycystic kidney disease (3)
-	1	-	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.7
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.69
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.22
Sift	Benign	0.31	T
Sift4G	Benign	0.37	T
Polyphen		0.074	B
Vest4		0.16
MVP		0.63
MPC		0.069
ClinPred		0.013	T
GERP RS		-5.0
Varity_R		0.035
gMVP		0.42
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201753421; hg19: chr6-51908518; COSMIC: COSV61872098;