rs73442356

Positions:

• chr6-51836485-C-G
• chr6-51836485-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.8108-16G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,582,314 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (81 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (70 hom.)
• Consequence: PKHD1 NM_138694.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.406

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-51836485-C-G is Benign according to our data. Variant chr6-51836485-C-G is described in ClinVar as [Benign]. Clinvar id is 262417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8108-16G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8108-16G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.8108-16G>C		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2664 AN: 152088 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00455 AC: 1142 AN: 250914 Hom.: 28 AF XY: 0.00339 AC XY: 459 AN XY: 135580

Gnomad AFR exome AF: 0.0588

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00194 AC: 2781 AN: 1430108 Hom.: 70 Cov.: 27 AF XY: 0.00176 AC XY: 1256 AN XY: 713562

Gnomad4 AFR exome AF: 0.0604

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000385

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.0175 AC: 2670 AN: 152206 Hom.: 81 Cov.: 33 AF XY: 0.0165 AC XY: 1231 AN XY: 74410

Gnomad4 AFR AF: 0.0611

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00102 Hom.: 2

Bravo AF: 0.0202

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2016	Variant summary: The PKHD1 c.8108-16G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 656/121014 control chromosomes (14 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0577145 (600/10396). This frequency is about 8 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Due to the lack of effect on amino acid sequence, the lack of predicted effect on splicing, and the high frequency of the variant in the control population, this variant has been classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.2
DANN	Benign	0.52

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: rs73442356; hg19: chr6-51701283;