6-52066088-TAAAA-TAA

Variant names:

• chr6-52066088-TAA-T
• rs5876252
• NM_138694.4:c.779-13_779-12delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_138694.4(PKHD1):​c.779-13_779-12delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 953,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.00300
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AFR (0.00457) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP6: Variant 6-52066088-TAA-T is Benign according to our data. Variant chr6-52066088-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 235729.Status of the report is criteria_provided_single_submitter, 1 stars.

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.779-13_779-12delTT		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.779-13_779-12delTT		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.779-13_779-12delTT		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.779-13_779-12delTT		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0000139 AC: 2 AN: 144006 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000692

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00247 AC: 436 AN: 176846 AF XY: 0.00262

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.00261

Gnomad EAS exome AF: 0.00132

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00256 AC: 2072 AN: 809094 Hom.: 0 AF XY: 0.00245 AC XY: 1042 AN XY: 425188

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00538 AC: 112 AN: 20810

American (AMR) AF: 0.00190 AC: 73 AN: 38374

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 30 AN: 20896

East Asian (EAS) AF: 0.000684 AC: 23 AN: 33638

South Asian (SAS) AF: 0.00276 AC: 185 AN: 67072

European-Finnish (FIN) AF: 0.00144 AC: 60 AN: 41796

Middle Eastern (MID) AF: 0.000972 AC: 4 AN: 4114

European-Non Finnish (NFE) AF: 0.00275 AC: 1498 AN: 544454

Other (OTH) AF: 0.00229 AC: 87 AN: 37940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000139 AC: 2 AN: 144038 Hom.: 0 Cov.: 0 AF XY: 0.0000287 AC XY: 2 AN XY: 69698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39162

American (AMR) AF: 0.0000691 AC: 1 AN: 14476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5006

South Asian (SAS) AF: 0.00 AC: 0 AN: 4510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66152

Other (OTH) AF: 0.00 AC: 0 AN: 1982

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00484 Hom.: 42

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive polycystic kidney disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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;