rs6935568

Variant names:

• chr6-51822354-C-T
• rs6935568
• NM_138694.4:c.8302+8507G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138694.4(PKHD1):​c.8302+8507G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 152,222 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.054 (235 hom., cov: 32)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.8302+8507G>A		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8302+8507G>A		intron	N/A	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8302+8507G>A		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.8302+8507G>A		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 8231 AN: 152104 Hom.: 233 Cov.: 32

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0459

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0542 AC: 8255 AN: 152222 Hom.: 235 Cov.: 32 AF XY: 0.0542 AC XY: 4029 AN XY: 74404

African (AFR) AF: 0.0646 AC: 2681 AN: 41522

American (AMR) AF: 0.0366 AC: 559 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3468

East Asian (EAS) AF: 0.0519 AC: 268 AN: 5168

South Asian (SAS) AF: 0.0705 AC: 340 AN: 4824

European-Finnish (FIN) AF: 0.0569 AC: 603 AN: 10600

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0524 AC: 3563 AN: 68030

Other (OTH) AF: 0.0487 AC: 103 AN: 2114

Alfa AF: 0.0511 Hom.: 365

Bravo AF: 0.0518

Asia WGS AF: 0.0940 AC: 326 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.60
PhyloP100		-0.076
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6935568; hg19: chr6-51687152;