6-52059976-A-G

Position:

chr6-52059976-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.409

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.1185T>C	p.Asp395=	synonymous_variant	15/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.1185T>C	p.Asp395=	synonymous_variant	15/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.965

AC:

146919

AN:

152180

Hom.:

71130

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.997

AC XY:

723137

AN XY:

725570

show subpopulations

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.:

AF XY:

0.967

AC XY:

72027

AN XY:

74466

show subpopulations

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

LINK: link

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 â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, 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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over