rs4715227

Variant names:

• chr6-51627086-T-C
• rs4715227
• NM_138694.4:c.11696A>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.11696A>G​(p.Gln3899Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,608,696 control chromosomes in the GnomAD database, including 243,945 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. Q3899P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (21359 hom., cov: 31)
  • Exomes 𝑓: 0.55 (222586 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.13
• Publications: 38 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=4.6837726E-5).
• BP6: Variant 6-51627086-T-C is Benign according to our data. Variant chr6-51627086-T-C is described in ClinVar as Benign. ClinVar VariationId is 96372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 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.11696A>G	p.Gln3899Arg	missense	Exon 66 of 67	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.11696A>G	p.Gln3899Arg	missense	Exon 66 of 67	ENSP00000360158.3	P08F94-1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80278 AN: 151796 Hom.: 21362 Cov.: 31

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.514

GnomAD2 exomes AF: 0.559 AC: 140351 AN: 251288 AF XY: 0.557

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.560

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.551 AC: 803362 AN: 1456782 Hom.: 222586 Cov.: 32 AF XY: 0.553 AC XY: 400989 AN XY: 725000

African (AFR) AF: 0.477 AC: 15897 AN: 33330

American (AMR) AF: 0.632 AC: 28231 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11928 AN: 26080

East Asian (EAS) AF: 0.559 AC: 22153 AN: 39652

South Asian (SAS) AF: 0.613 AC: 52833 AN: 86154

European-Finnish (FIN) AF: 0.525 AC: 28006 AN: 53388

Middle Eastern (MID) AF: 0.545 AC: 3139 AN: 5756

European-Non Finnish (NFE) AF: 0.550 AC: 608778 AN: 1107514

Other (OTH) AF: 0.538 AC: 32397 AN: 60240

GnomAD4 genome AF: 0.529 AC: 80300 AN: 151914 Hom.: 21359 Cov.: 31 AF XY: 0.527 AC XY: 39145 AN XY: 74238

African (AFR) AF: 0.480 AC: 19881 AN: 41426

American (AMR) AF: 0.576 AC: 8785 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3470

East Asian (EAS) AF: 0.557 AC: 2878 AN: 5166

South Asian (SAS) AF: 0.628 AC: 3023 AN: 4812

European-Finnish (FIN) AF: 0.505 AC: 5327 AN: 10546

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.548 AC: 37253 AN: 67942

Other (OTH) AF: 0.513 AC: 1081 AN: 2106

Alfa AF: 0.541 Hom.: 102801

Bravo AF: 0.532

TwinsUK AF: 0.553 AC: 2050

ALSPAC AF: 0.549 AC: 2114

ESP6500AA AF: 0.481 AC: 2120

ESP6500EA AF: 0.545 AC: 4690

ExAC AF: 0.555 AC: 67367

Asia WGS AF: 0.577 AC: 2007 AN: 3476

EpiCase AF: 0.542

EpiControl AF: 0.546

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	2	not specified (2)
-	-	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	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.000047	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.27
Sift	Benign	0.034	D
Sift4G	Benign	0.067	T
Polyphen		0.29	B
Vest4		0.13
MPC		0.094
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.42
Mutation Taster		=87/13	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: rs4715227; hg19: chr6-51491884; COSMIC: COSV64381846; COSMIC: COSV64381846;