6-51616055-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138694.4(PKHD1):c.*3026A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 151,902 control chromosomes in the GnomAD database, including 38,291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (38291 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.85

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-51616055-T-C is Benign according to our data. Variant chr6-51616055-T-C is described in ClinVar as [Benign]. Clinvar id is 357362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.*3026A>G		3_prime_UTR_variant	67/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.*3026A>G		3_prime_UTR_variant	67/67	1	NM_138694.4	P2
	ENST00000589278.6	n.811-6305T>C		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1	n.81-6300T>C		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1	n.221+5623T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.705 AC: 106933 AN: 151784 Hom.: 38265 Cov.: 30

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.657

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.704 AC: 107010 AN: 151902 Hom.: 38291 Cov.: 30 AF XY: 0.700 AC XY: 52001 AN XY: 74236

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.684

Gnomad4 ASJ AF: 0.576

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.589

Gnomad4 NFE AF: 0.653

Gnomad4 OTH AF: 0.655

Alfa AF: 0.694 Hom.: 4562

Bravo AF: 0.718

Asia WGS AF: 0.736 AC: 2558 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.10
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs2784199; hg19: chr6-51480853;