6-51615688-G-T

Variant names:

• chr6-51615688-G-T
• rs2784198
• NM_138694.4:c.*3393C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_138694.4(PKHD1):​c.*3393C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,046 control chromosomes in the GnomAD database, including 30,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.63 (30779 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.123

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]

ENSG00000228689 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-51615688-G-T is Benign according to our data. Variant chr6-51615688-G-T is described in ClinVar as [Benign]. Clinvar id is 357358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.*3393C>A		3_prime_UTR_variant	Exon 67 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117	c.*3393C>A		3_prime_UTR_variant	Exon 67 of 67	1	NM_138694.4	ENSP00000360158.3
ENSG00000228689	ENST00000454361.1	n.81-6667G>T		intron_variant	Intron 1 of 1	3
ENSG00000228689	ENST00000589278.6	n.811-6672G>T		intron_variant	Intron 2 of 2	5
ENSG00000228689	ENST00000650088.1	n.221+5256G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96474 AN: 151928 Hom.: 30765 Cov.: 32

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.635 AC: 96536 AN: 152046 Hom.: 30779 Cov.: 32 AF XY: 0.633 AC XY: 47033 AN XY: 74302

Gnomad4 AFR AF: 0.672

Gnomad4 AMR AF: 0.647

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.744

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.600

Alfa AF: 0.609 Hom.: 25691

Bravo AF: 0.642

Asia WGS AF: 0.715 AC: 2487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.36
CADD	Benign	6.1
DANN	Benign	0.81

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: rs2784198; hg19: chr6-51480486;