6-51856074-A-G

Variant names:

• chr6-51856074-A-G
• rs7452724
• NM_138694.4:c.7734-4T>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.7734-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,559,800 control chromosomes in the GnomAD database, including 108,806 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13545 hom., cov: 33)
  • Exomes 𝑓: 0.35 (95261 hom.)
• Consequence: PKHD1 NM_138694.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001209
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0490
• Publications: 17 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: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-51856074-A-G is Benign according to our data. Variant chr6-51856074-A-G is described in ClinVar as Benign. ClinVar VariationId is 96422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.7734-4T>C		splice_region intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.7734-4T>C		splice_region intron	N/A	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.7734-4T>C		splice_region intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.7734-4T>C		splice_region intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61227 AN: 151990 Hom.: 13536 Cov.: 33

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.445 AC: 111826 AN: 251142 AF XY: 0.436

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.868

Gnomad FIN exome AF: 0.450

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.346 AC: 487357 AN: 1407692 Hom.: 95261 Cov.: 28 AF XY: 0.351 AC XY: 246638 AN XY: 703294

African (AFR) AF: 0.410 AC: 13165 AN: 32120

American (AMR) AF: 0.634 AC: 28283 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6427 AN: 25848

East Asian (EAS) AF: 0.826 AC: 32313 AN: 39102

South Asian (SAS) AF: 0.510 AC: 43173 AN: 84610

European-Finnish (FIN) AF: 0.436 AC: 23273 AN: 53378

Middle Eastern (MID) AF: 0.264 AC: 1502 AN: 5686

European-Non Finnish (NFE) AF: 0.299 AC: 318475 AN: 1063922

Other (OTH) AF: 0.355 AC: 20746 AN: 58430

GnomAD4 genome AF: 0.403 AC: 61267 AN: 152108 Hom.: 13545 Cov.: 33 AF XY: 0.418 AC XY: 31063 AN XY: 74356

African (AFR) AF: 0.432 AC: 17920 AN: 41476

American (AMR) AF: 0.532 AC: 8133 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 902 AN: 3466

East Asian (EAS) AF: 0.852 AC: 4407 AN: 5174

South Asian (SAS) AF: 0.539 AC: 2602 AN: 4830

European-Finnish (FIN) AF: 0.452 AC: 4783 AN: 10578

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21554 AN: 67968

Other (OTH) AF: 0.367 AC: 776 AN: 2112

Alfa AF: 0.361 Hom.: 6104

Bravo AF: 0.408

Asia WGS AF: 0.624 AC: 2167 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.311

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 08, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Oct 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Polycystic kidney disease Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.7734-4T>C variant was identified in 43.42% of 52661 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015).

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.55
PhyloP100		-0.049
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.012
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: rs7452724; hg19: chr6-51720872;