6-51830998-TA-TAA

Variant names:

• chr6-51830998-T-TA
• rs566540835
• NM_138694.4:c.8174-10dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.8174-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,604,696 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (3 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.74
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 6-51830998-T-TA is Benign according to our data. Variant chr6-51830998-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197942.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00292 (444/151834) while in subpopulation AFR AF = 0.00965 (400/41468). AF 95% confidence interval is 0.00887. There are 4 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.8174-10dupT		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8174-10dupT		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.8174-10_8174-9insT		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.8174-10_8174-9insT		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 444 AN: 151716 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000898 AC: 221 AN: 246102 AF XY: 0.000721

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000939

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000436 AC: 634 AN: 1452862 Hom.: 3 Cov.: 29 AF XY: 0.000412 AC XY: 298 AN XY: 723046

African (AFR) AF: 0.0108 AC: 357 AN: 33178

American (AMR) AF: 0.000382 AC: 17 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25954

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39406

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86032

European-Finnish (FIN) AF: 0.0000940 AC: 5 AN: 53198

Middle Eastern (MID) AF: 0.000700 AC: 4 AN: 5714

European-Non Finnish (NFE) AF: 0.000175 AC: 193 AN: 1104928

Other (OTH) AF: 0.000734 AC: 44 AN: 59970

GnomAD4 genome AF: 0.00292 AC: 444 AN: 151834 Hom.: 4 Cov.: 32 AF XY: 0.00267 AC XY: 198 AN XY: 74196

African (AFR) AF: 0.00965 AC: 400 AN: 41468

American (AMR) AF: 0.00118 AC: 18 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67868

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.00357

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 17, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:1 Benign:1

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 20, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polycystic kidney disease 4 Benign:1

Jul 23, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism

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: rs566540835; hg19: chr6-51695796; COSMIC: COSV61879782;