chr6-51616527-A-ATT

Variant names:

• chr6-51616527-A-ATT
• rs113144792
• NM_138694.4:c.*2552_*2553dupAA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_138694.4(PKHD1):​c.*2552_*2553dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 359,846 control chromosomes in the GnomAD database, including 32 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (32 hom., cov: 28)
  • Exomes 𝑓: 0.012 (0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0187 (2642/141274) while in subpopulation AFR AF = 0.0258 (993/38504). AF 95% confidence interval is 0.0245. There are 32 homozygotes in GnomAd4. There are 1225 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

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.*2552_*2553dupAA		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.*2552_*2553dupAA		3_prime_UTR	Exon 67 of 67	ENSP00000360158.3	P08F94-1
	ENSG00000228689	ENST00000454361.1	TSL:3	n.81-5814_81-5813dupTT		intron	N/A
	ENSG00000228689	ENST00000589278.6	TSL:5	n.811-5819_811-5818dupTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2642 AN: 141226 Hom.: 31 Cov.: 28

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.0148

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00727

Gnomad EAS AF: 0.00184

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00916

Gnomad MID AF: 0.00993

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.0121 AC: 2635 AN: 218572 Hom.: 0 Cov.: 0 AF XY: 0.0119 AC XY: 1328 AN XY: 111144

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

African (AFR) AF: 0.0160 AC: 103 AN: 6420

American (AMR) AF: 0.0102 AC: 68 AN: 6670

Ashkenazi Jewish (ASJ) AF: 0.00744 AC: 61 AN: 8202

East Asian (EAS) AF: 0.00574 AC: 120 AN: 20906

South Asian (SAS) AF: 0.00927 AC: 19 AN: 2050

European-Finnish (FIN) AF: 0.0117 AC: 211 AN: 18092

Middle Eastern (MID) AF: 0.00710 AC: 8 AN: 1126

European-Non Finnish (NFE) AF: 0.0133 AC: 1871 AN: 140622

Other (OTH) AF: 0.0120 AC: 174 AN: 14484

⚠️ 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: 0.0187 AC: 2642 AN: 141274 Hom.: 32 Cov.: 28 AF XY: 0.0179 AC XY: 1225 AN XY: 68410

African (AFR) AF: 0.0258 AC: 993 AN: 38504

American (AMR) AF: 0.0133 AC: 187 AN: 14032

Ashkenazi Jewish (ASJ) AF: 0.00727 AC: 24 AN: 3300

East Asian (EAS) AF: 0.00185 AC: 9 AN: 4872

South Asian (SAS) AF: 0.0222 AC: 96 AN: 4324

European-Finnish (FIN) AF: 0.00916 AC: 80 AN: 8730

Middle Eastern (MID) AF: 0.0107 AC: 3 AN: 280

European-Non Finnish (NFE) AF: 0.0188 AC: 1210 AN: 64426

Other (OTH) AF: 0.0140 AC: 27 AN: 1926

Alfa AF: 0.00600 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

Splicing

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

Other links and lift over

dbSNP: rs113144792; hg19: chr6-51481325; COSMIC: COSV64391351;