rs1896976

Positions:

• chr6-52059976-A-G

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.1185T>C​(p.Asp395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,609,952 control chromosomes in the GnomAD database, including 794,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71173 hom., cov: 32)
  • Exomes 𝑓: 1.0 (723509 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.409

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-52059976-A-G is Benign according to our data. Variant chr6-52059976-A-G is described in ClinVar as [Benign]. Clinvar id is 96374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52059976-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.409 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1185T>C	p.Asp395=	synonymous_variant	15/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1185T>C	p.Asp395=	synonymous_variant	15/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.1185T>C	p.Asp395=	synonymous_variant	15/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.965 AC: 146919 AN: 152180 Hom.: 71130 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.973

GnomAD3 exomes AF: 0.990 AC: 248757 AN: 251196 Hom.: 123287 AF XY: 0.993 AC XY: 134796 AN XY: 135732

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1452054 AN: 1457654 Hom.: 723509 Cov.: 32 AF XY: 0.997 AC XY: 723137 AN XY: 725570

Gnomad4 AFR exome AF: 0.876

Gnomad4 AMR exome AF: 0.992

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.991

GnomAD4 genome AF: 0.965 AC: 147020 AN: 152298 Hom.: 71173 Cov.: 32 AF XY: 0.967 AC XY: 72027 AN XY: 74466

Gnomad4 AFR AF: 0.881

Gnomad4 AMR AF: 0.986

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.974

Alfa AF: 0.984 Hom.: 37834

Bravo AF: 0.960

Asia WGS AF: 0.993 AC: 3454 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -

Autosomal recessive polycystic kidney disease Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Feb 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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.Asp395= variant was identified in 29 of 258 proband chromosomes (frequency: 0.11) from individuals or families with ARPKD (Rossetti 2003, Losekoot 2005, Obeidova 2015). The variant was also identified in dbSNP (ID: rs1896976) as “With Benign allele”, ClinVar (4x, as benign, by EGL, Counsyl, Prevention Genetics, Illumina), RWTH AAachen University ARPKD database (115x, as polymorphism) databases. The variant was not identified in LOVD 3.0, databases. The variant was also identified by our laboratory in 19 individuals with ARPKD The variant was identified in control databases in 273534 of 276906 (135258 homozygous) chromosomes at a frequency of 0.987823 The variant was identified in the following populations at a frequency greater than 1%: African in 21039 of 24008 chromosomes (freq. 0.9), other in 6413 of 6458 chromosomes (freq. 0.99), Latino in 34151 of 34410 chromosomes (freq. 0.99), European in 126382 of 126462 chromosomes (freq. 0.99), Ashkenazi Jewish in 10130 of 10142 chromosomes (freq. 0.99), Eat Asian in 18862 of 18862 chromosomes (freq. 1), Finnish in 25784 of 25784 chromosomes (freq. 1),and South Asian in 30773 of 30784 chromosomes (freq. 0.99), increasing the likelihood this a benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp395Asp variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

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	-0.60
CADD	Benign	5.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1896976; hg19: chr6-51924774;