6-51868009-C-T

Position:

• chr6-51868009-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.7587G>A​(p.Gly2529Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,611,260 control chromosomes in the GnomAD database, including 284,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20786 hom., cov: 32)
  • Exomes 𝑓: 0.59 (263279 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.43

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-51868009-C-T is Benign according to our data. Variant chr6-51868009-C-T is described in ClinVar as [Benign]. Clinvar id is 96421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51868009-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.7587G>A	p.Gly2529Gly	synonymous_variant	48/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.7587G>A	p.Gly2529Gly	synonymous_variant	48/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.7587G>A	p.Gly2529Gly	synonymous_variant	48/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76144 AN: 151858 Hom.: 20777 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.787

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.499 AC: 124905 AN: 250528 Hom.: 34941 AF XY: 0.511 AC XY: 69243 AN XY: 135494

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.437

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.589 AC: 859478 AN: 1459284 Hom.: 263279 Cov.: 35 AF XY: 0.587 AC XY: 426066 AN XY: 726024

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.714

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.440

Gnomad4 FIN exome AF: 0.510

Gnomad4 NFE exome AF: 0.634

Gnomad4 OTH exome AF: 0.578

GnomAD4 genome AF: 0.501 AC: 76177 AN: 151976 Hom.: 20786 Cov.: 32 AF XY: 0.488 AC XY: 36264 AN XY: 74286

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.710

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.490

Gnomad4 NFE AF: 0.632

Gnomad4 OTH AF: 0.555

Alfa AF: 0.602 Hom.: 54209

Bravo AF: 0.490

Asia WGS AF: 0.320 AC: 1114 AN: 3478

EpiCase AF: 0.647

EpiControl AF: 0.637

ClinVar

Significance: Benign

Submissions summary: Benign:10

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.	May 11, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2016	Variant summary: The c.7587G>A (p.Gly2529=) in PKHD1 gene is a synonymous change that involves a non-conserved nucleotide with 4/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.506 (61140/120660 chrs tested) including numerous homozygous occurrences. This frequency greatly exceeds the maximal expected frequency of a pathogenic allele (0.007) in this gene. The variant of interest was cited as Benign by a reputable clinical laboratory. It is widely accepted as a rare polymorphism in the field. Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Polycystic kidney disease 4 Benign:2

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

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.7587G>A, p.Gly2529Gly variant was identified in 50.67% of 61140 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.4
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12210295; hg19: chr6-51732807; COSMIC: COSV61858770;