rs34548196

chr6-51619428-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):c.11878G>A(p.Val3960Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,762 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 33)
  • Exomes 𝑓: 0.018 (280 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.335

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004051566).
• BP6: Variant 6-51619428-C-T is Benign according to our data. Variant chr6-51619428-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51619428-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1790/152346) while in subpopulation NFE AF= 0.018 (1226/68030). AF 95% confidence interval is 0.0172. There are 17 homozygotes in gnomad4. There are 860 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.11878G>A	p.Val3960Ile	missense_variant	67/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.11878G>A	p.Val3960Ile	missense_variant	67/67	1	NM_138694.4	P2
	ENST00000589278.6	n.811-2932C>T		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1	n.81-2927C>T		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1	n.222-2927C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1788 AN: 152228 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0144 AC: 3603 AN: 250434 Hom.: 33 AF XY: 0.0147 AC XY: 1992 AN XY: 135334

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0181 AC: 26423 AN: 1461416 Hom.: 280 Cov.: 34 AF XY: 0.0179 AC XY: 13039 AN XY: 726944

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.00984

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0199

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0117 AC: 1790 AN: 152346 Hom.: 17 Cov.: 33 AF XY: 0.0115 AC XY: 860 AN XY: 74504

Gnomad4 AFR AF: 0.00368

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0163 Hom.: 37

Bravo AF: 0.0113

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0166 AC: 143

ExAC AF: 0.0141 AC: 1718

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -

Autosomal recessive polycystic kidney disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	This variant is associated with the following publications: (PMID: 26695994) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKHD1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.41
Dann	Benign	0.79
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.13
Sift	Benign	0.42	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.052
ClinPred		0.0020	T
GERP RS		0.43
Varity_R		0.025
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34548196; hg19: chr6-51484226; COSMIC: COSV99058309; COSMIC: COSV99058309;