6-51616517-T-C

Variant names:

• chr6-51616517-T-C
• rs1414504
• NM_138694.4:c.*2564A>G

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.*2564A>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 0.875 in 390,168 control chromosomes in the GnomAD database, including 149,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.88 (58880 hom., cov: 29)
  • Exomes 𝑓: 0.87 (90768 hom.)
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.297

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-51616517-T-C is Benign according to our data. Variant chr6-51616517-T-C is described in ClinVar as [Benign]. Clinvar id is 357368.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.*2564A>G		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.*2564A>G		3_prime_UTR_variant	Exon 67 of 67	1	NM_138694.4	ENSP00000360158.3
ENSG00000228689	ENST00000454361.1	n.81-5838T>C		intron_variant	Intron 1 of 1	3
ENSG00000228689	ENST00000589278.6	n.811-5843T>C		intron_variant	Intron 2 of 2	5
ENSG00000228689	ENST00000650088.1	n.222-5838T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.880 AC: 133504 AN: 151752 Hom.: 58844 Cov.: 29

Gnomad AFR AF: 0.917

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.851

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.833

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.877

Gnomad OTH AF: 0.845

GnomAD4 exome AF: 0.872 AC: 207770 AN: 238298 Hom.: 90768 Cov.: 0 AF XY: 0.871 AC XY: 105361 AN XY: 120934

Gnomad4 AFR exome AF: 0.912

Gnomad4 AMR exome AF: 0.839

Gnomad4 ASJ exome AF: 0.786

Gnomad4 EAS exome AF: 0.905

Gnomad4 SAS exome AF: 0.867

Gnomad4 FIN exome AF: 0.856

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.862

GnomAD4 genome AF: 0.880 AC: 133597 AN: 151870 Hom.: 58880 Cov.: 29 AF XY: 0.875 AC XY: 64883 AN XY: 74168

Gnomad4 AFR AF: 0.916

Gnomad4 AMR AF: 0.851

Gnomad4 ASJ AF: 0.777

Gnomad4 EAS AF: 0.883

Gnomad4 SAS AF: 0.870

Gnomad4 FIN AF: 0.833

Gnomad4 NFE AF: 0.877

Gnomad4 OTH AF: 0.846

Alfa AF: 0.890 Hom.: 7144

Bravo AF: 0.883

Asia WGS AF: 0.873 AC: 3037 AN: 3476

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	-0.90
CADD	Benign	1.8
DANN	Benign	0.72

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: rs1414504; hg19: chr6-51481315;