rs34460237

chr6-51659605-G-Achr6-51659605-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):c.10521C>T(p.His3507=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,518 control chromosomes in the GnomAD database, including 2,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (272 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2280 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.86

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]

LOC124900615 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-51659605-G-A is Benign according to our data. Variant chr6-51659605-G-A is described in ClinVar as [Benign]. Clinvar id is 96366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51659605-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.10521C>T	p.His3507=	synonymous_variant	61/67	ENST00000371117.8
LOC124900615	XR_926871.3	n.155+7232G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.10521C>T	p.His3507=	synonymous_variant	61/67	1	NM_138694.4	P2

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7389 AN: 152034 Hom.: 269 Cov.: 32

Gnomad AFR AF: 0.00912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0851

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0702

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0574

GnomAD3 exomes AF: 0.0661 AC: 16541 AN: 250142 Hom.: 737 AF XY: 0.0669 AC XY: 9042 AN XY: 135200

Gnomad AFR exome AF: 0.00950

Gnomad AMR exome AF: 0.0831

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.0749

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0712

GnomAD4 exome AF: 0.0480 AC: 70124 AN: 1461364 Hom.: 2280 Cov.: 33 AF XY: 0.0493 AC XY: 35818 AN XY: 726982

Gnomad4 AFR exome AF: 0.00756

Gnomad4 AMR exome AF: 0.0854

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.0736

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0589

GnomAD4 genome AF: 0.0487 AC: 7408 AN: 152154 Hom.: 272 Cov.: 32 AF XY: 0.0546 AC XY: 4064 AN XY: 74372

Gnomad4 AFR AF: 0.00910

Gnomad4 AMR AF: 0.0857

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.0713

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.0414

Gnomad4 OTH AF: 0.0582

Alfa AF: 0.0383 Hom.: 97

Bravo AF: 0.0433

Asia WGS AF: 0.102 AC: 355 AN: 3478

EpiCase AF: 0.0433

EpiControl AF: 0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2017	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1, p.His3507His variant was identified in 6.2% of 120686 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.056
Dann	Benign	0.27

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: rs34460237; hg19: chr6-51524403; COSMIC: COSV64382368;