rs201210830

Positions:

• chr6-51619200-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_138694.4(PKHD1):​c.12106C>T​(p.Arg4036Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 0.293

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]

ENSG00000228689 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024424195).
• BP6: Variant 6-51619200-G-A is Benign according to our data. Variant chr6-51619200-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406885.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.12106C>T	p.Arg4036Trp	missense_variant	67/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.12106C>T	p.Arg4036Trp	missense_variant	67/67	1	NM_138694.4	ENSP00000360158.3
ENSG00000228689	ENST00000454361.1	n.81-3155G>A		intron_variant		3
ENSG00000228689	ENST00000589278.6	n.811-3160G>A		intron_variant		5
ENSG00000228689	ENST00000650088.1	n.222-3155G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000722 AC: 11 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 250920 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000978 AC: 143 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.0000908 AC XY: 66 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00247

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000961

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PKHD1: PM2, BP4 -

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 09, 2020

Variant summary: PKHD1 c.12106C>T (p.Arg4036Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250920 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (7.6e-05 vs 0.0071), allowing no conclusion about variant significance. However, the variant was also reported in Japanese healthy control databases (HGVD-Kyoto and jMorp) with a frequency of 0.006 (including 1 homozygote in HGVD-Kyoto database). This frequency is somewhat close to the estimated maximal expected allele frequency for a pathogenic PKHD1 variant, therefore this variant might represent a benign polymorphism found primarily in populations of East Asian origin (HGVD). To our knowledge, no occurrence of c.12106C>T in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Polycystic kidney disease 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.84
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Benign	0.16	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.20
Sift	Benign	0.28	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.076
MVP		0.57
MPC		0.062
ClinPred		0.020	T
GERP RS		1.4
Varity_R		0.037
gMVP		0.065

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

Publications

LitVar

Other links and lift over

dbSNP: rs201210830; hg19: chr6-51483998;