rs3920621

Variant names:

• chr6-51775953-C-G
• rs3920621
• NM_138694.4:c.8441-32G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.8441-32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 984,000 control chromosomes in the GnomAD database, including 91,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (11127 hom., cov: 32)
  • Exomes 𝑓: 0.43 (80321 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.770
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-51775953-C-G is Benign according to our data. Variant chr6-51775953-C-G is described in ClinVar as Benign. ClinVar VariationId is 262421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8441-32G>C		intron_variant	Intron 53 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8441-32G>C		intron_variant	Intron 53 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8441-32G>C		intron_variant	Intron 53 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52305 AN: 151508 Hom.: 11132 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.345

GnomAD2 exomes AF: 0.445 AC: 107151 AN: 240598 AF XY: 0.449

Gnomad AFR exome AF: 0.0935

Gnomad AMR exome AF: 0.589

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.428 AC: 356043 AN: 832374 Hom.: 80321 Cov.: 11 AF XY: 0.432 AC XY: 189971 AN XY: 440000

African (AFR) AF: 0.0913 AC: 1973 AN: 21604

American (AMR) AF: 0.571 AC: 24570 AN: 43000

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 7019 AN: 22056

East Asian (EAS) AF: 0.633 AC: 23156 AN: 36598

South Asian (SAS) AF: 0.521 AC: 37966 AN: 72918

European-Finnish (FIN) AF: 0.435 AC: 21551 AN: 49498

Middle Eastern (MID) AF: 0.307 AC: 1405 AN: 4570

European-Non Finnish (NFE) AF: 0.410 AC: 222639 AN: 542616

Other (OTH) AF: 0.399 AC: 15764 AN: 39514

GnomAD4 genome AF: 0.345 AC: 52290 AN: 151626 Hom.: 11127 Cov.: 32 AF XY: 0.355 AC XY: 26282 AN XY: 74062

African (AFR) AF: 0.101 AC: 4190 AN: 41436

American (AMR) AF: 0.478 AC: 7263 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3470

East Asian (EAS) AF: 0.674 AC: 3468 AN: 5148

South Asian (SAS) AF: 0.533 AC: 2562 AN: 4810

European-Finnish (FIN) AF: 0.436 AC: 4588 AN: 10530

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28004 AN: 67732

Other (OTH) AF: 0.341 AC: 716 AN: 2100

Alfa AF: 0.373 Hom.: 2118

Bravo AF: 0.334

Asia WGS AF: 0.506 AC: 1754 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 4 Benign:2

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:1

Apr 12, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.30
DANN	Benign	0.71
PhyloP100		-0.77
BranchPoint Hunter		2.0
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: rs3920621; hg19: chr6-51640751; COSMIC: COSV61879949;