6-51934368-T-C

Variant names:

• chr6-51934368-T-C
• rs1266889
• NM_138694.4:c.5909-46A>G

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.5909-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 1,216,254 control chromosomes in the GnomAD database, including 281,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38157 hom., cov: 32)
  • Exomes 𝑓: 0.67 (243549 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.578
• Publications: 11 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=-0.86).
• BP6: Variant 6-51934368-T-C is Benign according to our data. Variant chr6-51934368-T-C is described in ClinVar as Benign. ClinVar VariationId is 262406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 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.5909-46A>G		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.5909-46A>G		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.5909-46A>G		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.5909-46A>G		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106930 AN: 152002 Hom.: 38114 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.941

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.640

GnomAD2 exomes AF: 0.706 AC: 173908 AN: 246412 AF XY: 0.696

Gnomad AFR exome AF: 0.774

Gnomad AMR exome AF: 0.811

Gnomad ASJ exome AF: 0.518

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.735

Gnomad NFE exome AF: 0.637

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.670 AC: 713082 AN: 1064134 Hom.: 243549 Cov.: 14 AF XY: 0.669 AC XY: 366912 AN XY: 548196

African (AFR) AF: 0.764 AC: 19655 AN: 25738

American (AMR) AF: 0.802 AC: 35323 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 12066 AN: 23672

East Asian (EAS) AF: 0.931 AC: 35232 AN: 37856

South Asian (SAS) AF: 0.708 AC: 55367 AN: 78214

European-Finnish (FIN) AF: 0.735 AC: 39023 AN: 53126

Middle Eastern (MID) AF: 0.507 AC: 1701 AN: 3356

European-Non Finnish (NFE) AF: 0.644 AC: 483682 AN: 750988

Other (OTH) AF: 0.658 AC: 31033 AN: 47150

GnomAD4 genome AF: 0.704 AC: 107029 AN: 152120 Hom.: 38157 Cov.: 32 AF XY: 0.711 AC XY: 52878 AN XY: 74366

African (AFR) AF: 0.770 AC: 31964 AN: 41504

American (AMR) AF: 0.737 AC: 11272 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1784 AN: 3470

East Asian (EAS) AF: 0.941 AC: 4849 AN: 5154

South Asian (SAS) AF: 0.721 AC: 3473 AN: 4814

European-Finnish (FIN) AF: 0.741 AC: 7846 AN: 10586

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43899 AN: 67976

Other (OTH) AF: 0.640 AC: 1351 AN: 2110

Alfa AF: 0.659 Hom.: 128149

Bravo AF: 0.705

Asia WGS AF: 0.811 AC: 2821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 4 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 19, 2021

Pars Genome 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.62
PhyloP100		0.58
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: rs1266889; hg19: chr6-51799166;