rs147487242

chr6-51912453-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):c.6245C>T(p.Thr2082Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,612,630 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0062 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (105 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.493

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034807324).
• BP6: Variant 6-51912453-G-A is Benign according to our data. Variant chr6-51912453-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197049.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}. Variant chr6-51912453-G-A is described in Lovd as [Benign]. Variant chr6-51912453-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.6245C>T	p.Thr2082Ile	missense_variant	38/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.6245C>T	p.Thr2082Ile	missense_variant	38/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.6245C>T	p.Thr2082Ile	missense_variant	38/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 942 AN: 151928 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00840

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00484

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0674

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00746 AC: 1875 AN: 251240 Hom.: 41 AF XY: 0.00720 AC XY: 978 AN XY: 135794

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00909

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00250

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0614

Gnomad NFE exome AF: 0.000942

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00282 AC: 4119 AN: 1460584 Hom.: 105 Cov.: 31 AF XY: 0.00276 AC XY: 2007 AN XY: 726700

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00949

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00564

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.0551

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00620 AC: 942 AN: 152046 Hom.: 15 Cov.: 32 AF XY: 0.00921 AC XY: 684 AN XY: 74306

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00852

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00466

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0674

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000880 Hom.: 2

Bravo AF: 0.00192

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00558 AC: 677

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	2.7
Dann	Benign	0.23
DEOGEN2	Uncertain	0.65	D;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.94	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.17
Sift	Benign	0.52	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0010	B;B
Vest4		0.10
MVP		0.68
MPC		0.064
ClinPred		0.0047	T
GERP RS		-3.3
Varity_R		0.045
gMVP		0.69

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: rs147487242; hg19: chr6-51777251;