6-51616527-A-AT

Variant names:

• chr6-51616527-A-AT
• rs113144792
• NM_138694.4:c.*2553dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_138694.4(PKHD1):​c.*2553dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 357,738 control chromosomes in the GnomAD database, including 658 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (653 hom., cov: 28)
  • Exomes 𝑓: 0.12 (5 hom.)
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0790
• Publications: 1 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000228689 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.*2553dupA		3_prime_UTR	Exon 67 of 67	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.*2553dupA		3_prime_UTR	Exon 67 of 67	ENSP00000360158.3	P08F94-1
	ENSG00000228689	ENST00000454361.1	TSL:3	n.81-5813dupT		intron	N/A
	ENSG00000228689	ENST00000589278.6	TSL:5	n.811-5818dupT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.100 AC: 14152 AN: 141108 Hom.: 654 Cov.: 28

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0977

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0331

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0871

GnomAD4 exome AF: 0.118 AC: 25656 AN: 216580 Hom.: 5 Cov.: 0 AF XY: 0.118 AC XY: 12983 AN XY: 110112

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

African (AFR) AF: 0.114 AC: 724 AN: 6344

American (AMR) AF: 0.105 AC: 690 AN: 6598

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 952 AN: 8130

East Asian (EAS) AF: 0.168 AC: 3472 AN: 20682

South Asian (SAS) AF: 0.0932 AC: 189 AN: 2028

European-Finnish (FIN) AF: 0.118 AC: 2108 AN: 17896

Middle Eastern (MID) AF: 0.0892 AC: 99 AN: 1110

European-Non Finnish (NFE) AF: 0.113 AC: 15733 AN: 139448

Other (OTH) AF: 0.118 AC: 1689 AN: 14344

⚠️ 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: 0.100 AC: 14167 AN: 141158 Hom.: 653 Cov.: 28 AF XY: 0.0984 AC XY: 6724 AN XY: 68340

African (AFR) AF: 0.101 AC: 3884 AN: 38498

American (AMR) AF: 0.0803 AC: 1125 AN: 14016

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 308 AN: 3300

East Asian (EAS) AF: 0.170 AC: 830 AN: 4870

South Asian (SAS) AF: 0.0914 AC: 395 AN: 4322

European-Finnish (FIN) AF: 0.0967 AC: 841 AN: 8700

Middle Eastern (MID) AF: 0.0357 AC: 10 AN: 280

European-Non Finnish (NFE) AF: 0.101 AC: 6520 AN: 64370

Other (OTH) AF: 0.0874 AC: 168 AN: 1922

Alfa AF: 0.0263 Hom.: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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		-0.079
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: rs113144792; hg19: chr6-51481325;