6-52066088-TAAAA-TAAAAAA

Variant names:

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

Variant summary

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

The NM_138694.4(PKHD1):​c.779-13_779-12dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 0)
  • Exomes 𝑓: 0.022 (1 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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_779-12dupTT		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.779-13_779-12dupTT		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_779-11insTT		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.779-12_779-11insTT		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 260 AN: 144014 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00199

Gnomad SAS AF: 0.000882

Gnomad FIN AF: 0.00318

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000801

Gnomad OTH AF: 0.00254

GnomAD2 exomes AF: 0.0185 AC: 3276 AN: 176846 AF XY: 0.0168

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0216

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0216 AC: 17413 AN: 807862 Hom.: 1 Cov.: 13 AF XY: 0.0204 AC XY: 8654 AN XY: 424464

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

African (AFR) AF: 0.0105 AC: 220 AN: 21028

American (AMR) AF: 0.0282 AC: 1078 AN: 38204

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 357 AN: 20884

East Asian (EAS) AF: 0.0229 AC: 765 AN: 33412

South Asian (SAS) AF: 0.0124 AC: 830 AN: 67128

European-Finnish (FIN) AF: 0.0213 AC: 879 AN: 41244

Middle Eastern (MID) AF: 0.0181 AC: 74 AN: 4082

European-Non Finnish (NFE) AF: 0.0228 AC: 12419 AN: 543980

Other (OTH) AF: 0.0209 AC: 791 AN: 37900

⚠️ 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: 0.00181 AC: 261 AN: 144046 Hom.: 1 Cov.: 0 AF XY: 0.00201 AC XY: 140 AN XY: 69714

African (AFR) AF: 0.00120 AC: 47 AN: 39166

American (AMR) AF: 0.00739 AC: 107 AN: 14476

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 9 AN: 3404

East Asian (EAS) AF: 0.00200 AC: 10 AN: 5006

South Asian (SAS) AF: 0.000887 AC: 4 AN: 4510

European-Finnish (FIN) AF: 0.00318 AC: 26 AN: 8176

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

European-Non Finnish (NFE) AF: 0.000801 AC: 53 AN: 66152

Other (OTH) AF: 0.00252 AC: 5 AN: 1984

Alfa AF: 0.0175 Hom.: 42

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5876252; hg19: chr6-51930886;