6-52066088-T-TA

Variant names:

• chr6-52066088-T-TA
• rs5876252
• NM_138694.4:c.779-12dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.779-12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (35007 hom., cov: 0)
  • Exomes 𝑓: 0.44 (4297 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.169
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 6-52066088-T-TA is Benign according to our data. Variant chr6-52066088-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1206384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 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.779-12dupT		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.779-12dupT		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.779-12_779-11insT		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.779-12_779-11insT		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.691 AC: 99469 AN: 143940 Hom.: 35028 Cov.: 0

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.730

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.717

GnomAD2 exomes AF: 0.458 AC: 80941 AN: 176846 AF XY: 0.456

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.473

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.468

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.444 AC: 358782 AN: 807850 Hom.: 4297 Cov.: 13 AF XY: 0.445 AC XY: 188844 AN XY: 424266

African (AFR) AF: 0.336 AC: 6991 AN: 20794

American (AMR) AF: 0.466 AC: 17869 AN: 38376

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 9377 AN: 20774

East Asian (EAS) AF: 0.469 AC: 15672 AN: 33440

South Asian (SAS) AF: 0.426 AC: 28365 AN: 66636

European-Finnish (FIN) AF: 0.461 AC: 19211 AN: 41650

Middle Eastern (MID) AF: 0.479 AC: 1962 AN: 4100

European-Non Finnish (NFE) AF: 0.445 AC: 242460 AN: 544254

Other (OTH) AF: 0.446 AC: 16875 AN: 37826

GnomAD4 genome AF: 0.691 AC: 99450 AN: 143972 Hom.: 35007 Cov.: 0 AF XY: 0.693 AC XY: 48296 AN XY: 69694

African (AFR) AF: 0.503 AC: 19689 AN: 39110

American (AMR) AF: 0.794 AC: 11494 AN: 14480

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2552 AN: 3406

East Asian (EAS) AF: 0.806 AC: 4033 AN: 5004

South Asian (SAS) AF: 0.703 AC: 3166 AN: 4504

European-Finnish (FIN) AF: 0.754 AC: 6168 AN: 8184

Middle Eastern (MID) AF: 0.707 AC: 191 AN: 270

European-Non Finnish (NFE) AF: 0.758 AC: 50134 AN: 66128

Other (OTH) AF: 0.714 AC: 1416 AN: 1984

Alfa AF: 0.371 Hom.: 42

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease 4 (2)
-	-	1	Autosomal recessive polycystic kidney disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
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: rs5876252; hg19: chr6-51930886;